Indole and benzimidazole derivatives

ABSTRACT

The present invention relates to new indole and benzimidazole compounds and pharmaceutically acceptable salts, esters or prodrugs thereof, compositions of the new compounds together with pharmaceutically acceptable carriers, and uses of the new compounds. The compounds of the invention have the following general formula:

This application claims the benefit under 35 U.S.C. § 119(e) of U.S.Provisional Application No. 60/620,385 filed on Oct. 19, 2004, which ishereby incorporated by reference in its entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to substituted indole and benzimidazolecompounds as well as pharmaceutically acceptable salts, esters, isomers,mixtures of isomers, derivatives, and prodrugs thereof, compositions ofthese compounds together with pharmaceutically acceptable carriers, anduses of these compounds.

2. State of the Art

Kinesins are motor proteins that use adenosine triphosphate to bind tomicrotubules and generate mechanical force. Kinesins are characterizedby a motor domain having about 350 amino acid residues. The crystalstructures of several kinesin motor domains have been resolved.

Currently, about one hundred kinesin-related proteins (KRP) have beenidentified. Kinesins are involved in a variety of cell biologicalprocesses including transport of organelles and vesicles, andmaintenance of the endoplasmic reticulum. Several KRPs interact with themicrotubules of the mitotic spindle or with the chromosomes directly andappear to play a pivotal role during the mitotic stages of the cellcycle. These mitotic KRPs are of particular interest for the developmentof cancer therapeutics.

Kinesin spindle protein (KSP) (also known as Eg5, HsEg5, KNSL1, orKIF11) is one of several kinesin-like motor proteins that are localizedto the mitotic spindle and known to be required for formation and/orfunction of the bipolar mitotic spindle.

In 1995, the depletion of KSP using an antibody directed against theC-terminus of KSP was shown to arrest HeLa cells in mitosis withmonoastral microtubule arrays (Blangy et al., Cell 83:1159-1169, 1995).Mutations in bimC and cut7 genes, which are considered to be homologuesof KSP, cause failure in centrosome separation in Aspergillus nidulans(Enos, A. P., and N. R. Morris, Cell 60:1019-1027, 1990) andSchizosaccharomyces pombe (Hagan, I., and M. Yanagida, Nature347:563-566, 1990). Treatment of cells with either ATRA (alltrans-retinoic acid), which reduces KSP expression on the protein level,or depletion of KSP using antisense oligonucleotides revealed asignificant growth inhibition in DAN-G pancreatic carcinoma cellsindicating that KSP might be involved in the antiproliferative action ofATRA (Kaiser, A., et al., J. Biol. Chem. 274, 18925-18931, 1999).Interestingly, the Xenopus laevis Aurora-related protein kinase pEg2 wasshown to associate and phosphorylate XlEg5 (Giet, R., et al., J. Biol.Chem. 274:15005-15013, 1999). Potential substrates of Aurora-relatedkinases are of particular interest for cancer drug development. Forexample, Aurora 1 and 2 kinases are overexpressed on the protein and RNAlevel and the genes are amplified in colon cancer patients.

The first cell permeable small molecule inhibitor for KSP, “monastrol,”was shown to arrest cells with monopolar spindles without affectingmicrotubule polymerization as do conventional chemotherapeutics such astaxanes and vinca alkaloids (Mayer, T. U., et al., Science 286:971-974,1999). Monastrol was identified as an inhibitor in phenotype-basedscreens and it was suggested that this compound may serve as a lead forthe development of anticancer drugs. The inhibition was determined notto be competitive in respect to adenosine triphosphate and to be rapidlyreversible (DeBonis, S., et al., Biochemistry, 42:338-349, 2003; Kapoor,T. M., et al., J. Cell Biol., 150:975-988, 2000).

In light of the importance of improved chemotherapeutics, there is aneed for KSP inhibitors that are effective in vivo inhibitors of KSP andKSP-related proteins.

SUMMARY OF THE INVENTION

This invention is directed to indole and benzimidazole compounds whichmodulate the activity of KSP represented by formula I:

wherein:

W is ═CH— or ═N—;

R¹ is selected from the group consisting of aminoacyl, acylamino,carboxyl, carboxyl ester, aryl, and alkyl optionally substituted withhydroxy or halo;

R² is selected from the group consisting of hydrogen, optionallysubstituted alkyl, and aryl;

R³ is —X-A, wherein A is selected from the group consisting of alkyl,aryl, heteroaryl, heterocyclic, and cycloalkyl, all of which may beoptionally substituted with 1 to 4 substituents independently selectedfrom the group consisting of alkyl, substituted alkyl, acylamino,heterocyclic, substituted heterocyclic, heterocyclyloxy, substitutedheterocyclyloxy, acyl, carboxyl, carboxyl ester, oxo (except as asubstituent on substituted aryl or substituted heteroaryl), halo,hydroxy, and nitro;

X is selected from the group consisting of —C(O)—, —C(S)—, —S(O)—,—S(O)₂—, and —S(O)₂NR—, where R is hydrogen or alkyl and when X is—C(O)—, A is further selected from the group consisting of amino,substituted amino, alkoxy, and substituted alkoxy;

R⁴ is selected from the group consisting of hydrogen, hydroxy, acyl,alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, andsubstituted heterocyclic;

or R¹ and R⁴, together with the carbon atom attached to R¹ and thenitrogen atom attached to R⁴ form a group selected from the groupconsisting of heterocyclic, substituted heterocyclic, heteroaryl, andsubstituted heteroaryl;

or when R¹ and R⁴, together with the carbon attached to R¹ and nitrogenatom attached to R⁴ do not form a group selected from the groupconsisting of heterocyclic, substituted heterocyclic, heteroaryl, andsubstituted heteroaryl, then R³ and R⁴, together with the nitrogen atombound thereto, form a group selected from the group consisting ofheterocyclic, substituted heterocyclic, heteroaryl, and substitutedheteroaryl;

R⁵ is -L-A¹ where L is selected from the group consisting of —S(O)_(r)—where r is one or two and C₁ to C₂ straight chain alkylene, optionallysubstituted with hydroxy, halo and acylamino;

A¹ is selected from the group consisting of aryl, substituted aryl,heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic, cycloalkyl and substituted cycloalkyl;

each R⁶ is independently selected from the group consisting of acyl,acylamino, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, amino,substituted amino, aminoacyl, aryl, substituted aryl, aryloxy,substituted aryloxy, carboxyl, carboxyl ester, cyano, cycloalkyl,substituted cycloalkyl, halo, heteroaryl, substituted heteroaryl,heteroaryloxy, substituted heteroaryloxy, heterocyclic, substitutedheterocyclic, heterocyclyloxy, substituted heterocyclyloxy, hydroxy,nitro, thiol, alkylthio, substituted alkylthio, arylthio, substitutedarylthio, heteroarylthio, and substituted heteroarylthio;

p is equal to 0, 1, 2 or 3;

or pharmaceutically acceptable salts, esters and prodrugs thereof;

with the proviso that when W is ═N—, and A¹ is substituted phenyl, saidsubstituted phenyl does not include an ortho substituent of the formula-Q-NR⁷R⁸ where Q is a bond, C₁ to C₃ alkyl, C₂ to C₃ alkenyl, C₂ to C₃alkynyl and R⁷ and R⁸ are independently C₁ to C₈ alkyl or C₁ to C₈cycloalkyl optionally substituted with 1 to 3 substituents selected fromthe group consisting of hydroxy, halo, amino, cyano, nitro, C₁ to C₈alkyl, C₁ to C₈ cycloalkyl, halo C₁ to C₈ alkyl, C₁ to C₈ alkoxy, haloC₁ to C₈ alkoxy, or R⁷ and R⁸ jointly with the nitrogen atom to whichthey are bound form an optionally substituted 3- to 7-memberedheterocyclic or an optionally substituted 3- to 7-membered heteroaryl.

DETAILED DESCRIPTION OF THE INVENTION A. Compounds of the Invention

As stated above, compounds of the invention include those of formula I:

wherein:

W is ═CH— or ═N—;

R¹ is selected from the group consisting of aminoacyl, acylamino,carboxyl, carboxyl ester, aryl, and alkyl optionally substituted withhydroxy or halo;

R² is selected from the group consisting of hydrogen, optionallysubstituted alkyl, and aryl;

R³ is —X-A, wherein A is selected from the group consisting of alkyl,aryl, heteroaryl, heterocyclic, and cycloalkyl, all of which may beoptionally substituted with 1 to 4 substituents independently selectedfrom the group consisting of alkyl, substituted alkyl, acylamino,heterocyclic, substituted heterocyclic, heterocyclyloxy, substitutedheterocyclyloxy, acyl, carboxyl, carboxyl ester, oxo (except as asubstituent on substituted aryl or substituted heteroaryl), halo,hydroxy, and nitro;

X is selected from the group consisting of —C(O)—, —C(S)—, —S(O)—,—S(O)₂—, and —S(O)₂NR—, where R is hydrogen or alkyl and when X is—C(O)—, A is further selected from the group consisting of amino,substituted amino, alkoxy, and substituted alkoxy;

R⁴ is selected from the group consisting of hydrogen, hydroxy, acyl,alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, andsubstituted heterocyclic;

or R¹ and R⁴, together with the carbon atom attached to R¹ and thenitrogen atom attached to R⁴ form a group selected from the groupconsisting of heterocyclic, substituted heterocyclic, heteroaryl, andsubstituted heteroaryl;

or when R¹ and R⁴, together with the carbon attached to R¹ and nitrogenatom attached to R⁴ do not form a group selected from the groupconsisting of heterocyclic, substituted heterocyclic, heteroaryl, andsubstituted heteroaryl, then R³ and R⁴, together with the nitrogen atombound thereto, form a group selected from the group consisting ofheterocyclic, substituted heterocyclic, heteroaryl, and substitutedheteroaryl;

R⁵ is -L-A¹ where L is selected from the group consisting of —S(O)_(r)—where r is one or two and C₁ to C₂ straight chain alkylene, optionallysubstituted with hydroxy, halo and acylamino;

A¹ is selected from the group consisting of aryl, substituted aryl,heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic, cycloalkyl and substituted cycloalkyl;

each R⁶ is independently selected from the group consisting of acyl,acylamino, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, amino,substituted amino, aminoacyl, aryl, substituted aryl, aryloxy,substituted aryloxy, carboxyl, carboxyl ester, cyano, cycloalkyl,substituted cycloalkyl, halo, heteroaryl, substituted heteroaryl,heteroaryloxy, substituted heteroaryloxy, heterocyclic, substitutedheterocyclic, heterocyclyloxy, substituted heterocyclyloxy, hydroxy,nitro, thiol, alkylthio, substituted alkylthio, arylthio, substitutedarylthio, heteroarylthio, and substituted heteroarylthio;

p is equal to 0, 1, 2 or 3;

or pharmaceutically acceptable salts, esters and prodrugs thereof;

with the proviso that when W is ═N—, and A¹ is substituted phenyl, saidsubstituted phenyl does not include an ortho substituent of the formula-Q-NR⁷R⁸ where Q is a bond, C₁ to C₃ alkyl, C₂ to C₃ alkenyl, C₂ to C₃alkynyl and R⁷ and R⁸ are independently C₁ to C₈ alkyl or C₁ to C₈cycloalkyl optionally substituted with 1 to 3 substituents selected fromthe group consisting of hydroxy, halo, amino, cyano, nitro, C₁ to C₈alkyl, C₁ to C₈ cycloalkyl, halo C₁ to C₈ alkyl, C₁ to C₈ alkoxy, haloC₁ to C₈ alkoxy, or R⁷ and R⁸ jointly with the nitrogen atom to whichthey are bound form an optionally substituted 3- to 7-memberedheterocyclic or an optionally substituted 3- to 7-membered heteroaryl.

In one embodiment, this invention is directed to benzimidazole compoundsof formula IA:

wherein R¹, R², R³, R⁴, R⁵, R⁶ and p are as defined above.

In another embodiment, this invention is directed to indole compounds offormula IB:

wherein R¹, R², R³, R⁴, R⁵, R⁶ and p are as defined above.

In yet another embodiment, the invention is directed to a compound offormula IC:

wherein

W is ═CH— or ═N—;

p is equal to 0, 1, 2 or 3;

R⁹ is alkyl or substituted alkyl;

R¹¹ is —X¹-A², wherein X¹ is —C(O)— and A² is selected from the groupconsisting of alkyl, substituted alkyl, aryl, substituted aryl,heteroaryl, and substituted heteroaryl;

R¹² is selected from the group consisting of hydrogen, -alkylene-amino,-alkylene-substituted amino, -alkylene-aryl, -alkylene-substituted aryl,-alkylene-heteroaryl, and -alkylene-substituted heteroaryl;

or R⁹ and R¹² together with the carbon atom attached to R⁹ and thenitrogen atom attached to R¹² form a group selected from the groupconsisting of heterocyclic, substituted heterocyclic, heteroaryl, andsubstituted heteroaryl;

or when R⁹ and R¹² together with the carbon atom attached to R⁹ and thenitrogen atom attached to R¹² do not form a group selected from thegroup consisting of heterocyclic, substituted heterocyclic, heteroaryl,and substituted heteroaryl, then R¹¹ and R¹², together with the nitrogenatom bound thereto join to form a group selected from the groupconsisting of heterocyclic, substituted heterocyclic, heteroaryl, andsubstituted heteroaryl;

R¹³ is -L¹-A³, wherein L¹ is —S(O)_(r)— where r is 1 or 2 or C₁ to C₂straight chain alkylene, and A³ is selected from the group consisting ofaryl, substituted aryl, heteroaryl, and substituted heteroaryl;

each R¹⁴ is independently selected from the group consisting of halo, C₂to C₃ alkynyl, C₂ to C₃ alkenyl, C₁ to C₅ alkyl, C₁ to C₃ alkoxy, andphenyl;

or pharmaceutically acceptable salts, esters or prodrugs thereof;

with the proviso that when W is ═N—, and A¹ is substituted phenyl, saidsubstituted phenyl does not include an ortho substituent of the formula-Q-NR⁷R⁸ where Q is a bond, C₁ to C₃ alkyl, C₂ to C₃ alkenyl, C₂ to C₃alkynyl and R⁷ and R⁸ are independently C₁ to C₈ alkyl or C₁ to C₈cycloalkyl optionally substituted with 1 to 3 substituents selected fromthe group consisting of hydroxy, halo, amino, cyano, nitro, C₁ to C₈alkyl, C₁ to C₈ cycloalkyl, halo C₁ to C₈ alkyl, C₁ to C₈ alkoxy, haloC₁ to C₈ alkoxy, or R⁷ and R⁸ jointly with the nitrogen atom to whichthey are bound form an optionally substituted 3- to 7-memberedheterocyclic or an optionally substituted 3- to 7-membered heteroaryl.

In formulas I, IA, IB and/or IC the following embodiments either aloneor in combination with other embodiments include the following:

1. R¹ (R⁹)

In some embodiments of the invention, R¹ is alkyl or aryl or R¹ isethyl, isopropyl, t-butyl, or phenyl and is preferably, derived from thecorresponding L-amino acid.

2. R²

In some embodiments R² is hydrogen or methyl. In some embodiments, R² isalkyl.

3. R³ (R¹¹)

In some embodiments, X is —C(O)— and A is aryl or heteroaryl optionallysubstituted with halo, alkyl, acylamino, nitro, or hydroxy.

In other embodiments, R³ is selected from the group consisting of(2-chloro-6-methylpyridin-4-yl)carbonyl;(5-methylimidazol-4-yl)carbonyl; (dimethylamino)methylcarbonyl;(naphth-2-yl)carbonyl; (pyridin-3-yl)carbonyl; (pyridin-4-yl)carbonyl;1,5-dimethylpyrazol-3-ylcarbonyl;1-methyl-5-trifluoromethylpyrazol-4-ylcarbonyl;1-methyl-5-chloropyrazol-4-ylcarbonyl;2-(2-aminoethylamido)-4-methylbenzoyl; 2,4-difluorobenzoyl;2,4-dimethylthiazol-5-ylcarbonyl; 2,6-difluorobenzoyl;2-aminoethylcarbonyl; 2-aminothiazol-4-ylcarbonyl; 2-chlorobenzoyl;2-chloropyridin-5-ylcarbonyl; 2-fluorobenzoyl; 2-methoxybenzoyl;2-methylpyridin-5-ylcarbonyl; 3,4-dichlorobenzoyl; 3,4-dimethylbenzoyl;3-chlorobenzoyl; 3-fluoro-4-methylbenzoyl;3-hydroxypyridin-4-ylcarbonyl; 4-aminopyridin-3-ylcarbonyl;4-bromobenzoyl; 4-chlorobenzoyl; 4-chloropyridin-3-ylcarbonyl;4-dimethylaminobenzoyl; 4-hydroxybenzoyl; 4-hydroxypyridin-3-ylcarbonyl;4-methoxybenzoyl; 4-methyl-2-(aminoethylcarbonylamino)benzoyl;4-methylbenzoyl; 4-methylisoxazol-3-ylcarbonyl;4-methylpyridin-3-ylcarbonyl; 4-morpholino-N-ylpyridin-3-ylcarbonyl;4-nitrobenzoyl; 4-t-butylbenzoyl; 4-trifluoromethylbenzoyl;4-trifluoromethylpyridin-3-ylcarbonyl; 5-chloropyridin-3-ylcarbonyl;5-methylpyrazol-3-ylcarbonyl; 6-chloropyridin-3-ylcarbonyl; benzoyl;cyclohexylcarbonyl; furan-3-ylcarbonyl; isoxazol-3-ylcarbonyl;phenylsulfonyl; piperidin-4-ylcarbonyl; pyrazin-2-ylcarbonyl;pyridazin-3-ylcarbonyl; pyridazin-4-ylcarbonyl;tetrahydrofuran-2-ylcarbonyl; tetrahydrofuran-3-ylcarbonyl; andthiazol-4-ylcarbonyl.

Additional embodiments of R³ include the following moieties:

where

indicates the point of attachment.

Particularly preferred embodiments include X-A being selected from thegroup consisting of 2-aminoethylcarbonyl;4-methyl-2-(aminoethylcarbonylamino)benzoyl; (naphth-2-yl)carbonyl;(pyridin-3-yl)carbonyl; (pyridin-4-yl)carbonyl;2-(2-aminoethylamido)-4-methylbenzoyl; 2,4-difluorobenzoyl;2,6-difluorobenzoyl; 2-fluorobenzoyl; 3,4-dimethylbenzoyl;3-fluoro-4-methylbenzoyl; 4-bromobenzoyl; 4-chlorobenzoyl;4-hydroxybenzoyl; 4-methylbenzoyl; 4-nitrobenzoyl; and benzoyl.

4. R¹ and R⁴ (R⁹ and R¹²)

R¹ and R⁴, together with the carbon atom attached to R¹ and the nitrogenatom attached to R⁴ form a heterocyclic or substituted heterocyclicgroup and in one embodiment the group is 3-hydroxy-pyrrolidinyl.

5. R³ and R⁴ (R¹¹ and R¹²)

In embodiments when R¹ and R⁴ are not cyclized as described above, thenR³ and R⁴ together with the nitrogen atom attached thereto can join toform a substituted heterocyclic group. In one embodiment the group is2-aminoethyl-5-methyl-8-oxo-7H-quinazolin-1-yl.

6. R⁴ (R¹¹)

In one embodiment, R⁴ is selected from the group consisting of hydrogen,alkyl and substituted alkyl.

In other embodiments, R⁴ is selected from the group consisting ofhydrogen; (aminomethylcarbonyl)aminoethyl;2,2-dimethyl-3-(4-methylpiperazin-1-yl)propyl;2,2-dimethyl-3-dimethylaminopropyl; 2-aminoethyl;2-hydroxyethyl-3-aminopropyl; 2-hydroxypyridin-4-ylmethyl;2-hydroxypyridin-5-ylmethyl; 3-(1-cyanourea)propyl;3-(benzylamino)propyl; 3-(cyclobutylamino)propyl;3-(cyclohexylmethylamino)propyl; 3-(diethylamino)propyl;3-(isopropylamino)propyl; 3-(phenylcarbonyloxy)propyl;3-[(3-trifluoromethylpyridin-6-yl)amino]propyl;3-[(5-pyridin-3-yloxyindazol-3-yl)methylamino]propyl;3-[(6-fluoroindazol-3-yl)methylamino]propyl;3-[(aminomethyl-carbonyl)amino]propyl; 3-[5-cyanopyridin-2-yl]propyl;3-{[5-(pyridin-3-yloxy)indazol-3-yl]methylamino]propyl;3-amino-3-(aminocarbonyl-methyl)propyl; 3-aminopropyl; 3hydroxypropyl;3-methylsulfonylaminopropyl; 3-ureapropyl; 4-methylbenzyl;5-methoxyindazol-3-ylmethyl; benzyl; piperidin-3-ylmethyl;piperidin-4-yl; pyrrolidin-2-ylmethyl;

where

indicates the point of attachment.

More preferably, R⁴ is selected from the group consisting of hydrogen;3-(1-cyanourea)propyl; 3-(benzylamino)propyl; 3-(cyclobutylamino)propyl;3-(cyclohexylmethylamino)propyl; 3-(diethylamino)propyl;3-(isopropylamino)propyl; 3-aminopropyl; 3-ureapropyl; 4-methylbenzyl;and imidazol-4-ylmethyl.

7. R⁵ (R¹³)

In one embodiment of the invention L is —SO₂— or —CH₂— and A¹ isoptionally substituted aryl. In other embodiments, R⁵ is selected fromthe group consisting of 2,4-difluorobenzyl; 2-methylbenzyl;3-(methylamido)benzyl; 3,5-difluorobenzyl; 3-chlorobenzyl;3-fluorobenzyl; 3-hydroxybenzyl; 3-methylbenzyl; 4-chlorobenzyl;4-methylbenzyl; benzyl; and thiazol-4-ylmethyl.

Particularly preferred R⁵ groups are selected from the group consistingof: 3-(methylamido)benzyl; 3,5-difluorobenzyl; 3-chlorobenzyl;3-fluorobenzyl; 3-hydroxybenzyl; 4-chlorobenzyl; and benzyl.

8. R⁶

When p is not zero, then R⁶ is selected from the group consisting ofpropargyl; bromo; —CF₃; chloro; ethyl; ethynyl; fluoro; methoxy; methyl;phenyl; and vinyl.

In some embodiments, R⁶ is selected from the following bromo; chloro;ethyl; methoxy; methyl; propargyl; vinyl; fluoro; and phenyl.

9. R¹⁴

In some embodiments, R¹⁴ is propargyl, bromo, —CF₃, chloro, ethyl,ethynyl, fluoro, methoxy, methyl, phenyl, or vinyl. In some embodiments,R¹⁴ is bromo, chloro, ethyl, methoxy, methyl, propargyl, vinyl, fluoro,or phenyl.

10. p

In some embodiments, p is zero or one.

Indole and benzimidazole compounds within the scope of this inventionare exemplified by those set forth in Tables 1 and 2 as follows. TABLE 1

Cmpd No. R¹ R³ R⁴ R⁵ R⁶ 1 isopropyl 4-chlorobenzoyl 3-aminopropyl benzylH 2 isopropyl 4-methylbenzoyl 3-aminopropyl benzyl H 3 isopropyl4-methylbenzoyl 3-aminopropyl benzyl 5-methyl 4 isopropyl4-methylbenzoyl 3-aminopropyl benzyl 5-chloro 5 isopropyl4-methylbenzoyl 3-aminopropyl 4-chlorobenzyl 6-fluoro 6 ethyl4-methylbenzoyl 3-aminopropyl benzyl 5-chioro 7 isopropyl 4-bromobenzoyl3-aminopropyl benzyl H 8 isopropyl 4-methylbenzoyl 3-aminopropyl benzyl5-bromo 9 ethyl benzoyl 3-aminopropyl benzyl 5-bromo 10 ethyl4-methylbenzoyl 3-aminopropyl benzyl 5-bromo 11 isopropyl4-methylbenzoyl 3-aminopropyl 3-hydroxybenzyl 5-methyl 12 isopropyl4-methylbenzoyl 3-aminopropyl 3-fluorobenzyl 5-methyl 13 isopropyl4-methylbenzoyl 3-aminopropyl benzyl 5-ethyl 14 isopropyl4-methylbenzoyl 3-aminopropyl 3-hydroxybenzyl 5-ethyl 15 isopropyl4-methylbenzoyl 3-ammopropyl 3-fluorobenzyl 5-ethyl 16 isopropyl2-aminoethylcarbonyl 4-methylbenzyl benzyl 5-bromo 17 isopropyl4-methylbenzoyl 3-aminopropyl benzyl 5-vinyl 18 isopropyl4-methylbenzoyl 3-aminopropyl benzyl 5-methoxy 19 isopropyl4-methylbenzoyl 3-aminopropyl benzyl phenyl 20 isopropyl 4-methyl-2- Hbenzyl 5-bromo (aminoethylcarbonylamino)- benzoyl 21 R¹/R⁴ = 4-4-methylbenzoyl — 3-hydroxybenzyl 5-methyl hydroxypyrrolidin- 2-yl 22isopropyl 4-methylbenzoyl 3-aminopropyl benzyl 5-propargyl 23 isopropylR³/R⁴ = 2-aminoethyl-5- — benzyl 5-bromo methyl-8-oxo-7H-quinazolin-1-yl 24 isopropyl 3-fluoro-4-methylbenzoyl 3-aminopropyl3-fluorobenzyl 5-methyl 25 isopropyl benzoyl 3-aminopropyl3-fluorobenzyl 5-methyl 26 isopropyl 2,4-difluorobenzoyl 3-aminopropyl3-fluorobenzyl 5-methyl 27 isopropyl 3,4-dimethylbenzoyl 3-aminopropyl3-fluorobenzyl 5-methyl 28 isopropyl 4-methylbenzoyl 3-aminopropyl3-(methylamido) 5-bromo benzyl 29 isopropyl 2,6-difluorobenzoyl3-aminopropyl 3-fluorobenzyl 5-methyl 30 isopropyl 2-fluorobenzoyl3-aminopropyl 3-fluorobenzyl 5-methyl 31 isopropyl benzoyl 3-aminopropyl3-chlorobenzyl 5-bromo 32 isopropyl 4-nitrobenzoyl 3-aminopropyl3-fluorobenzyl 5-methyl 33 isopropyl (pyridin-3-yl)carbonyl3-aminopropyl 3-fluorobenzyl 5-methyl 34 isopropyl(pyridin-4-yl)carbonyl 3-aminopropyl 3-fluorobenzyl 5-methyl 35isopropyl (naphth-2-yl)carbonyl 3-aminopropyl 3-fluorobenzyl 5-methyl 36t-butyl benzoyl 3-aminopropyl 3-fluorobenzyl 5-methyl 37 isopropyl4-hydroxybenzoyl 3-aminopropyl 3-fluorobenzyl 5-methyl 38 isopropyl4-methylbenzoyl 3-(benzylamino)propyl benzyl 5-chloro 39 isopropyl4-methylbenzoyl 3- benzyl 5-chloro (cyclohexylmethylamino) propyl 40t-butyl benzoyl 3-aminopropyl benzyl H 41 isopropyl 4-methylbenzoyl3-(isopropylamino) benzyl 5-chloro propyl 42 isopropyl 4-methylbenzoyl3-(diethylamino)propyl benzyl 5-chloro 43 isopropyl 4-methylbenzoyl3-(cyclobutylamino) benzyl 5-chloro propyl 44 isopropyl benzoyl3-aminopropyl 3,5- 5-bromo difluorobenzyl 48 isopropyl 4-methylbenzoyl3-(N-cyanourea)propyl benzyl 5-chloro 49 isopropyl 4-methylbenzoyl3-ureapropyl benzyl 5-chloro 50 isopropyl benzoyl imidazol-4-ylmethyl3-fluorobenzyl 5-methylThe symbol (*) indicates a chiral center. Unless otherwise indicated,this chiral center contemplates both the (R) and the (S) configurationas well as mixtures thereof. Other chiral centers may also be present inthe compound and unless otherwise indicated, the (R) and the (S)configuration are contemplated.

TABLE 2

Cmpd No. Y R¹ R³ R⁴ R⁵ 45 5-chloro isopropyl benzoyl 3-aminopropylbenzyl 46 5-chloro isopropyl 4- 3-aminopropyl benzyl methylbenzoyl 475-chloro isopropyl benzoyl 3-aminopropyl phenyl- sulfonylThe symbol (*) indicates a chiral center. Unless otherwise indicated,this chiral center contemplates both the (R) and the (S) configurationas well as mixtures thereof. Other chiral centers may also be present inthe compound and unless otherwise indicated, the (R) and the (S)configuration are contemplated.

Representative Compounds of the Invention

Specific compounds within the scope of this invention are exemplified inTable 3 in the experimental section.

ALTERNATIVE EMBODIMENTS

In an alternative embodiment, the invention relates to compounds of theinvention include those of formula II:

wherein:

R¹⁵ is selected from the group consisting of aminoacyl, acylamino,carboxyl, carboxyl ester, aryl, C₁ to C₈ alkyl optionally substitutedwith hydroxy or halo;

R¹⁶ is selected from the group consisting of hydrogen, C₁ to C₈ alkyl,and aryl;

R¹⁷ is —X²-A³, wherein A³ is selected from the group consisting ofalkyl, aryl, heteroaryl, heterocyclic, and cycloalkyl, all of which maybe optionally substituted with 1 to 4 substituents independentlyselected from the group consisting of C₁ to C₈ alkyl, C₁ to C₈substituted alkyl, C₁ to C₈ alkoxy, C₁ to C₈ substituted alkoxy, amino,substituted amino, heterocyclic, substituted heterocyclic,heterocyclyloxy, substituted heterocyclyloxy, acyl, carboxyl, carboxylester, oxo (not included as a substituent on substituted aryl orsubstituted heteroaryl), halo, hydroxy, and nitro, and X² is selectedfrom the group consisting of —C(O)—, —C(S)—, —S(O)—, —S(O)₂—, and—S(O)₂NR—, where R is hydrogen or C₁ to C₈ alkyl and when X² is —C(O)—,A³ is further selected from the group consisting of amino, substitutedamino, alkoxy, and substituted alkoxy;

R¹⁸ is selected from the group consisting of hydrogen,alkylene-aminoacyl, alkylene-oxyacyl, alkylene-OH,[alkylene]_(q)-nitrogen-containing heterocyclic,-[alkylene]_(q)-substituted nitrogen-containing heterocyclic,-[alkylene]_(q)-nitrogen containing heteroaryl,-[alkylene]_(q)-substituted nitrogen-containing heteroaryl,-[alkylene]_(q)-NR¹⁹R²⁰, -[alkylene]_(q)-aryl, and-[alkylene]_(q)-substituted aryl, wherein q is zero or one, alkylene isa C₁ to C₈ straight chain alkylene group optionally mono ordisubstituted with one or two substituents independently selected fromthe group consisting of amino, substituted amino, hydroxy, alkyl,substituted alkyl, carboxyl, carboxyl ester, oxo, and halo, R¹⁹ and R²⁰are independently selected from the group consisting of hydrogen, C₁ toC₈ alkyl, C₁ to C₈ substituted alkyl, cyano, aminoacyl, —S(O)-alkyl,—S(O)-substituted alkyl, —S(O)₂-alkyl, —S(O)₂-substituted alkyl,heterocyclic, substituted heterocyclic, acyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, cycloalkyl and substitutedcycloalkyl or when R¹⁹ is hydrogen, R²⁰ is further selected from thegroup consisting of hydroxy, alkoxy, or substituted alkoxy;

or R¹⁵ and R¹⁸, together with the carbon atom attached to R¹⁵ and thenitrogen atom attached to R¹⁸ form a heterocyclic, unsaturatedheterocyclic, substituted heterocyclic or substituted unsaturatedheterocyclic group;

R¹⁹ is -L²-A⁴ where L² is selected from the group consisting of—S(O)_(r)— where r is one or two and C₁ to C₂ straight chain alkylene,optionally substituted with hydroxy, halo or acylamino and A⁴ isselected from the group consisting of aryl, substituted aryl,heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic, cycloalkyl and substituted cycloalkyl;

W is ═CH— or ═N—;

Y is selected from the group consisting of acyl, acylamino, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, alkoxy, substituted alkoxy, amino, substituted amino,aminoacyl, aryl, substituted aryl, aryloxy, substituted aryloxy,carboxyl, carboxyl ester, cyano, cycloalkyl, substituted cycloalkyl,halo, heteroaryl, substituted heteroaryl, heteroaryloxy, substitutedheteroaryloxy, heterocyclic, substituted heterocyclic, heterocyclyloxy,substituted heterocyclyloxy, hydroxy, nitro, thiol, alkylthio,substituted alkylthio, arylthio, substituted arylthio, heteroarylthio,and substituted heteroarylthio;

t is equal to 0, 1, 2 or 3;

provided that when W is ═N—, and A⁴ is substituted phenyl, saidsubstituted phenyl does not include an ortho substituent of the formulaQ-NR²²R²³ where Q is a bond, C₁ to C₃ alkyl, C₂ to C₃ alkenyl, C₂ to C₃alkynyl and R²² and R²³ are independently C₁ to C₈ alkyl or C₁ to C₈cycloalkyl optionally substituted with 1 to 3 substituents selected fromthe group consisting of hydroxy, halo, amino, cyano, nitro, C₁ to C₈alkyl, C₁ to C₈ cycloalkyl, halo-C₁ to C₈ alkyl, C₁ to C₈ alkoxy,halo-C₁ to C₈ alkoxy, or R²² and R²³ jointly with the nitrogen atom towhich they are bound form a 3 to 7 membered heterocyclic group;

or pharmaceutically acceptable salts, esters and prodrugs thereof.

Methods and Compositions of the Invention

Also provided is a composition comprising a compound of formula I, IA,IB and IC (including mixtures and/or salts thereof) and apharmaceutically acceptable excipient or carrier.

In another aspect, the present invention provides methods of treating amammalian patient suffering from a disorder mediated, at least in part,by KSP. Thus, the present invention provides methods of treating amammalian patient in need of such treatment comprising administering tothe patient a therapeutically effective amount of a compound of formulaI, IA, IB, IC and/or II (including mixtures thereof) either alone or incombination with other anticancer agents.

B. Definitions and Overview

As discussed above, the present invention is directed to new substitutedimidazole compounds.

It is to be understood that the terminology used herein is for thepurpose of describing particular embodiments only and is not intended tolimit the scope of the present invention. It must be noted that as usedherein and in the claims, the singular forms “a,” and “the” includeplural referents unless the context clearly dictates otherwise. In thisspecification and in the claims which follow, reference will be made toa number of terms which shall be defined to have the following meanings:

As used herein, “alkyl” refers to monovalent saturated aliphatichydrocarbyl groups having from 1 to 8 carbon atoms, preferably 1 to 6,and more preferably 1 to 3 carbon atoms. The alkyl group may be straightchain or branched. This term is exemplified by groups such as methyl,ethyl, n-propyl, iso-propyl, n-butyl, t-butyl, n-pentyl and the like.

“Substituted alkyl” refers to an alkyl group having from 1 to 3, andpreferably 1 to 2, substituents selected from the group consisting ofalkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substitutedamino, aminoacyl, aryl, substituted aryl, aryloxy, substituted aryloxy,cyano, halogen, hydroxy, nitro, carboxyl, carboxyl ester, cycloalkyl,substituted cycloalkyl, spirocycloalkyl, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, —SO₂-alkyl, and—SO₂-substituted alkyl.

“Alkylene” refers to divalent saturated aliphatic hydrocarbyl groupspreferably having from 1 to 5 and more preferably 1 to 3 carbon atomswhich are either straight-chained or branched. This term is exemplifiedby groups such as methylene (—CH₂—), ethylene (—CH₂CH₂—), n-propylene(—CH₂CH₂CH₂—), iso-propylene (—CH₂CH(CH₃)—) or (—CH(CH₃)CH₂—) and thelike.

“Alkoxy” refers to the group “alkyl-O-” which includes, by way ofexample, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, t-butoxy,sec-butoxy, n-pentoxy and the like.

“Substituted alkoxy” refers to the group “substituted alkyl-O—”.

“Acyl” refers to the groups H—C(O)—, alkyl-C(O)—, substitutedalkyl-C(O)—, alkenyl-C(O)—, substituted alkenyl-C(O)—, alkynyl-C(O)—,substituted alkynyl-C(O)-cycloalkyl-C(O)—, substituted cycloalkyl-C(O)—,aryl-C(O)—, substituted aryl-C(O)—, heteroaryl-C(O)—, substitutedheteroaryl-C(O)—, heterocyclic-C(O)—, and substitutedheterocyclic-C(O)—, wherein alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

“Aminoacyl” refers to the group —C(O)NR³⁰R³⁰ where each R³⁰ isindependently selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl,heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic and where each R³⁰ is joined to form together with thenitrogen atom a heterocyclic or substituted heterocyclic ring whereinalkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic andsubstituted heterocyclic are as defined herein.

“Acyloxy” refers to the groups alkyl-C(O)O—, substituted alkyl-C(O)O—,alkenyl-C(O)O—, substituted alkenyl-C(O)O—, alkynyl-C(O)O—, substitutedalkynyl-C(O)O—, aryl-C(O)O—, substituted aryl-C(O)O—, cycloalkyl-C(O)O—,substituted cycloalkyl-C(O)O—, heteroaryl-C(O)O—, substitutedheteroaryl-C(O)O—, heterocyclic-C(O)O—, and substitutedheterocyclic-C(O)O— wherein alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

“Oxyacyl” or “carboxyl ester” refers to the groups —C(O)O-alkyl,—C(O)O-substituted alkyl, —C(O)O-alkenyl, —C(O)O-substituted alkenyl,—C(O)O-alkynyl, —C(O)O-substituted alkynyl, —C(O)O-aryl,—C(O)O-substituted aryl, —C(O)O-cycloalkyl, —C(O)O-substitutedcycloalkyl, —C(O)O-heteroaryl, —C(O)O-substituted heteroaryl,—C(O)O-heterocyclic, and —C(O)O-substituted heterocyclic wherein alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, heterocyclic and substitutedheterocyclic are as defined herein.

“Alkenyl” refers to alkenyl groups having from 2 to 6 carbon atoms andpreferably 2 to 4 carbon atoms and having at least 1 and preferably from1 to 2 sites of alkenyl unsaturation. Such groups are exemplified byvinyl, allyl, but-3-en-1-yl, and the like.

“Substituted alkenyl” refers to alkenyl groups having from 1 to 3substituents, and preferably 1 to 2 substituents, selected from thegroup consisting of alkoxy, substituted alkoxy, acyl, acylamino,acyloxy, amino, substituted amino, aminoacyl, aryl, substituted aryl,aryloxy, substituted aryloxy, cyano, halogen, hydroxy, nitro, carboxyl,carboxyl ester, cycloalkyl, substituted cycloalkyl, heteroaryl,substituted heteroaryl, heterocyclic, and substituted heterocyclic withthe proviso that any hydroxy substitution is not attached to a vinyl(unsaturated) carbon atom.

“Alkynyl” refers to alkynyl groups having from 2 to 6 carbon atoms andpreferably 2 to 3 carbon atoms and having at least 1 and preferably from1 to 2 sites of alkynyl unsaturation. Examples of alkynyl include, butare not limited to, propargyl, butyne, pentyne, etc.

“Substituted alkynyl” refers to alkynyl groups having from 1 to 3substituents, and preferably 1 to 2 substituents, selected from thegroup consisting of alkoxy, substituted alkoxy, acyl, acylamino,acyloxy, amino, substituted amino, aminoacyl, aryl, substituted aryl,aryloxy, substituted aryloxy, cyano, halogen, hydroxy, nitro, carboxyl,carboxyl ester, cycloalkyl, substituted cycloalkyl, heteroaryl,substituted heteroaryl, heterocyclic, and substituted heterocyclic withthe proviso that any hydroxy substitution is not attached to anacetylenic carbon atom.

“Amino” refers to the group —NH₂.

“Cyano” refers to the group —CN.

“Substituted amino” refers to the group —NR³¹R³² where R³¹ and R³² areindependently selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl,heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic, cyano, aminoacyl, —SO₂-alkyl, —SO₂-substituted alkyl, andwhere R³¹ and R³² are joined, together with the nitrogen bound theretoto form a heterocyclic or substituted heterocyclic group provided thatR³¹ and R³² are both not hydrogen. When R³¹ is hydrogen and R³² isalkyl, the substituted amino group is sometimes referred to herein asalkylamino. When R³¹ and R³² are alkyl, the substituted amino group issometimes referred to herein as dialkylamino. When referring to amonosubstituted amino, it is meant that either R³¹ or R³² is hydrogenbut not both. When referring to a disubstituted amino, it is meant thatneither R³¹ or R³² is hydrogen.

“Acylamino” refers to the groups —NR³³C(O)alkyl, —NR³³C(O)substitutedalkyl, —NR³³C(O)cycloalkyl, —NR³³C(O)substituted cycloalkyl,—NR³³C(O)alkenyl, —NR³³C(O)substituted alkenyl, —NR³³C(O)alkynyl,—NR³³C(O)substituted alkynyl, —NR³³C(O)aryl, —NR³³C(O)substituted aryl,—NR³³C(O)heteroaryl, —NR³³C(O)substituted heteroaryl,—NR³³C(O)heterocyclic, and —NR³³C(O)substituted heterocyclic where R³³is hydrogen or alkyl and wherein alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

“Nitro” refers to the group —NO₂.

“Aryl” or “Ar” refers to a monovalent aromatic carbocyclic group of from6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiplecondensed rings (e.g., naphthyl or anthryl) in which the condensed ringsmay or may not be aromatic (e.g., 2-benzoxazolinone,2H-1,4-benzoxazin-3(4H)-one-7-yl, and the like) provided that the pointof attachment is at an aromatic carbon atom. Preferred aryls includephenyl and naphthyl.

“Substituted aryl” refers to aryl groups which are substituted with from1 to 3 substituents, and preferably 1 to 2 substituents, selected fromthe group consisting of hydroxy, acyl, acylamino, acyloxy, alkyl,substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, amino, substituted amino,aminoacyl, aryl, substituted aryl, aryloxy, substituted aryloxy,carboxyl, carboxyl ester, cyano, thiol, alkylthio, substitutedalkylthio, arylthio, substituted arylthio, heteroarylthio, substitutedheteroarylthio, cycloalkylthio, substituted cycloalkylthio,heterocyclicthio, substituted heterocyclicthio, cycloalkyl, substitutedcycloalkyl, halo, nitro, heteroaryl, substituted heteroaryl,heterocyclic, substituted heterocyclic, heteroaryloxy, substitutedheteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, aminosulfonyl (NH₂—SO₂—), and substituted amino sulfonyl.

“Aryloxy” refers to the group aryl-O— that includes, by way of example,phenoxy, naphthoxy, and the like.

“Substituted aryloxy” refers to substituted aryl-O— groups.

“Carboxyl” refers to —COOH or salts thereof.

“Carboxyl ester” refers to —COOR³³, where R³³ is defined above.

“Cycloalkyl” refers to cyclic alkyl groups of from 3 to 10 carbon atomshaving single or multiple cyclic rings including, by way of example,adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl and thelike.

“Spirocycloalkyl” refers to cyclic groups from 3 to 10 carbon atomshaving a cycloalkyl ring with a spiro union (the union formed by asingle atom which is the only common member of the rings) as exemplifiedby the following structure:

“Substituted cycloalkyl” refers to a cycloalkyl group, having from 1 to5 substituents selected from the group consisting of alkyl, substitutedalkyl, oxo (═O), thioxo (═S), alkoxy, substituted alkoxy, acyl,acylamino, acyloxy, amino, substituted amino, aminoacyl, aryl,substituted aryl, aryloxy, substituted aryloxy, cyano, halogen, hydroxy,nitro, carboxyl, carboxyl esters, cycloalkyl, substituted cycloalkyl,heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic, —SO₂-alkyl and —SO₂-cycloalkyl

“Halo” or “halogen” refers to fluoro, chloro, bromo and iodo andpreferably is fluoro or chloro.

The term “haloalkyl” refers to a branched, straight-chain or cyclicalkyl group, substituted with 1 or more halogen atoms (e.g., “halo C₁ toC₈ alkyl” groups have from 1 to 8 carbon atoms). The term “haloalkoxy”refers to a haloalkyl group as defined above attached via an oxygenbridge. “Halo C₁ to C₈ alkoxy” groups have 1 to 8 carbon atoms.

“Hydroxy” or “hydroxyl” refers to the group —OH.

“Heteroaryl” refers to an aromatic group of from 1 to 10 carbon atomsand 1 to 4 heteroatoms selected from the group consisting of oxygen,nitrogen and sulfur within the ring. Such heteroaryl groups can have asingle ring (e.g., pyridinyl or furyl) or multiple condensed rings(e.g., indolizinyl or benzothienyl) wherein the condensed rings may ormay not be aromatic and/or contain a heteroatom provided that the pointof attachment is through an atom of the aromatic heteroaryl group. Inone embodiment, the nitrogen and/or the sulfur ring atom(s) of theheteroaryl group are optionally oxidized to provide for the N-oxide(N→O), sulfinyl, or sulfonyl moieties. Preferred heteroaryls includepyridinyl, pyrrolyl, indolyl, thiophenyl, and furanyl.

“Substituted heteroaryl” refers to heteroaryl groups that aresubstituted with from 1 to 3 substituents selected from the same groupof substituents defined for substituted aryl.

The term “nitrogen-containing heteroaryl” refers to a heteroaryl groupwherein at least one of the ring members is a nitrogen. The term“substituted nitrogen-containing heteroaryl” refers to a substitutedheteroaryl group wherein at least one ring member is a nitrogen.

“Heteroaryloxy” refers to the group —O-heteroaryl and “substitutedheteroaryloxy” refers to the group —O-substituted heteroaryl whereinheteroaryl and substituted heteroaryl are as defined herein.

“Heterocycle” or “heterocyclic” or “heterocycloalkyl” or “heterocyclyl”refers to a saturated or unsaturated (but not aromatic) group having asingle ring or multiple condensed rings, including fused, pendant, andspiro ring systems, from 1 to 10 carbon atoms and from 1 to 4 heteroatoms selected from the group consisting of nitrogen, sulfur or oxygenwithin the ring wherein, in fused ring systems, one ring is aheterocyclic ring and one or more the rings can be cycloalkyl, aryl orheteroaryl. In one embodiment, the nitrogen and/or sulfur atom(s) of theheterocyclic group are optionally oxidized to provide for the N-oxide,sulfinyl, and sulfonyl moieties.

“Substituted heterocyclic” or “substituted heterocycloalkyl” or“substituted heterocyclyl” refers to heterocyclyl groups that aresubstituted with from 1 to 3 of the same substituents as defined forsubstituted cycloalkyl.

Examples of heterocyclyls and heteroaryls include, but are not limitedto, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine,pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole,indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine,naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine,carbazole, carboline, phenanthridine, acridine, phenanthroline,isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine,imidazolidine, imidazoline, piperidine, piperazine, indoline,phthalimide, 1,2,3,4-tetrahydroisoquinoline,4,5,6,7-tetrahydrobenzo[b]thiophene, thiazole, thiazolidine, thiophene,benzo[b]thiophene, morpholinyl, thiomorpholinyl (also referred to asthiamorpholinyl), 1,1-dioxothiomorpholinyl, piperidinyl, pyrrolidine,tetrahydrofuranyl, and the like.

The term “nitrogen-containing heterocyclic” refers to a heterocyclicgroup wherein at least one of the ring members is a nitrogen atom. Theterm “substituted nitrogen-containing heterocyclic” refers to asubstituted heterocyclic group wherein at least one of the ring membersis a nitrogen atom.

“Thiol” refers to the group —SH.

“Alkylthio” or “thioalkoxy” refers to the group —S-alkyl.

“Substituted alkylthio” or “substituted thioalkoxy” refers to the group—S-substituted alkyl.

“Arylthio” refers to the group —S-aryl, where aryl is defined above.

“Substituted arylthio” refers to the group —S-substituted aryl, wheresubstituted aryl is defined above.

“Heteroarylthio” refers to the group —S-heteroaryl, where heteroaryl isdefined above.

“Substituted heteroarylthio” refers to the group —S-substitutedheteroaryl, where substituted heteroaryl is defined above.

“Heterocyclicthio” refers to the group —S-heterocyclic and “substitutedheterocyclicthio” refers to the group —S-substituted heterocyclic, whereheterocyclic and substituted heterocyclic are defined above.

“Heterocyclyloxy” refers to the group heterocyclyl-O— and “substitutedheterocyclyloxy refers to the group substituted heterocyclyl-O— whereheterocyclyl and substituted heterocyclyl are defined above.

“Cycloalkylthio” refers to the group —S-cycloalkyl and “substitutedcycloalkylthio” refers to the group —S-substituted cycloalkyl, wherecycloalkyl and substituted cycloalkyl are defined above.

“Biological activity” as used herein refers to an inhibitionconcentration when tested in at least one of the assays outlined inExample 7 or 8 or a decrease in optical density as tested in Example 9.

As used herein, the term “pharmaceutically acceptable salts” refers tothe nontoxic acid or alkaline earth metal salts of the compounds offormula I, IA, IB, IC and II. These salts can be prepared in situ duringthe final isolation and purification of the compounds of formula I, IA,IB, IC and II, or by separately reacting the base or acid functions witha suitable organic or inorganic acid or base, respectively.Representative salts include, but are not limited to, the following:acetate, adipate, alginate, citrate, aspartate, benzoate,benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate,digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate,glucoheptanoate, glycerophosphate, hemi-sulfate, heptanoate, hexanoate,fumarate, hydrochloride, hydrobromide, hydroiodide,2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate,nicotinate, 2-napth-alenesulfonate, oxalate, pamoate, pectinate,persulfate, 3-phenylproionate, picrate, pivalate, propionate, succinate,sulfate, tartrate, thiocyanate, p-toluenesulfonate and undecanoate.Also, the basic nitrogen-containing groups can be quarternized with suchagents as alkyl halides, such as methyl, ethyl, propyl, and butylchloride, bromides, and iodides; dialkyl sulfates like dimethyl,diethyl, dibutyl, and diamyl sulfates, long chain halides such as decyl,lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkylhalides like benzyl and phenethyl bromides, and others. Water oroil-soluble or dispersible products are thereby obtained.

Examples of acids that may be employed to form pharmaceuticallyacceptable acid addition salts include such inorganic acids ashydrochloric acid, sulfuric acid and phosphoric acid and such organicacids as oxalic acid, maleic acid, methanesulfonic acid, succinic acidand citric acid. Basic addition salts can be prepared in situ during thefinal isolation and purification of the compounds of formula I, IA, IB,IC and II, or separately by reacting carboxylic acid moieties with asuitable base such as the hydroxide, carbonate or bicarbonate of apharmaceutically acceptable metal cation or with ammonia, or an organicprimary, secondary or tertiary amine. Pharmaceutically acceptable saltsinclude, but are not limited to, cations based on the alkali andalkaline earth metals, such as sodium, lithium, potassium, calcium,magnesium, aluminum salts and the like, as well as ammonium, quaternaryammonium, and amine cations, including, but not limited to ammonium,tetramethylammonium, tetraethylammonium, methylamine, dimethylamine,trimethylamine, triethylamine, ethylamine, and the like. Otherrepresentative organic amines useful for the formation of base additionsalts include diethylamine, ethylenediamine, ethanolamine,diethanolamine, piperazine and the like.

As used herein, the term “pharmaceutically acceptable ester” refers toesters which hydrolyze in vivo and include those that break down in thehuman body to leave the parent compound, a salt thereof, or apharmaceutically active metabolite. Suitable ester groups include, forexample, those derived from pharmaceutically acceptable aliphaticcarboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic andalkanedioic acids, in which each alkyl or alkenyl moiety advantageouslyhas not more than 6 carbon atoms. Representative examples of particularesters include, but are not limited to, formates, acetates, propionates,butyrates, acrylates and ethylsuccinates.

The term “pharmaceutically acceptable prodrug” as used herein refers tothose prodrugs of the compounds of the present invention which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of humans and lower animals without undue toxicity,irritation, allergic response, and the like, commensurate with areasonable benefit/risk ratio, and effective for their intended use, aswell as the zwitterionic forms, where possible, of the compounds of theinvention. The term “prodrug” refers to compounds that are rapidlytransformed in vivo to yield the parent compound or a pharmaceuticallyactive metabolite of the above formula, for example by hydrolysis inblood. A discussion is provided in T. Higuchi and V. Stella, Pro-drugsas Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, andin Edward B. Roche, ed., Bioreversible Carriers in Drug Design, AmericanPharmaceutical Association and Pergamon Press, 1987, both of which areincorporated herein by reference.

As used herein “anticancer agents” or “agent for the treatment ofcancer” refers to agents that include, by way of example only, agentsthat induce apoptosis; polynucleotides (e.g., ribozymes); polypeptides(e.g., enzymes); drugs; biological mimetics; alkaloids; alkylatingagents; antitumor antibiotics; antimetabolites; hormones; platinumcompounds; monoclonal antibodies conjugated with anticancer drugs,toxins, and/or radionuclides; biological response modifiers (e.g.interferons and interleukins, etc.); adoptive immunotherapy agents;hematopoietic growth factors; agents that induce tumor celldifferentiation (e.g. all-trans-retinoic acid, etc.); gene therapyreagents; antisense therapy reagents and nucleotides; tumor vaccines;inhibitors of angiogenesis, and the like. Numerous other agents are wellwithin the purview of one of skill in the art.

It is understood that in all substituted groups defined above, polymersarrived at by defining substituents with further substituents tothemselves (e.g., substituted aryl having a substituted aryl group as asubstituent which is itself substituted with a substituted aryl group,etc.) are not intended for inclusion herein. In such cases, the maximumnumber of such substituents is three. That is to say that each of theabove definitions is constrained by a limitation that, for example,substituted aryl groups are limited to -substituted aryl-(substitutedaryl)-substituted aryl.

Similarly, it is understood that the above definitions are not intendedto include impermissible substitution patterns (e.g., methyl substitutedwith 5 fluoro groups or a hydroxy group alpha to ethenylic or acetylenicunsaturation). Such impermissible substitution patterns are well knownto the skilled artisan.

Compounds of this invention may exhibit stereoisomerism by virtue of thepresence of one or more asymmetric or chiral centers in the compounds.The present invention contemplates the various stereoisomers andmixtures thereof. Certain of the compounds of the invention compriseasymmetrically substituted carbon atoms. Such asymmetrically substitutedcarbon atoms can result in the compounds of the invention comprisingmixtures of stereoisomers at a particular asymmetrically substitutedcarbon atom or a single stereoisomer. As a result, racemic mixtures,mixtures of diastereomers, single enantiomer, as well as singlediastereomers of the compounds of the invention are included in thepresent invention. The terms “S” and “R” configuration, as used herein,are as defined by the IUPAC 1974 “RECOMMENDATIONS FOR SECTION E,FUNDAMENTAL STEREOCHEMISTRY ,” Pure Appl. Chem. 45:13-30, 1976. Desiredenantiomers can be obtained by chiral synthesis from commerciallyavailable chiral starting materials by methods well known in the art, ormay be obtained from mixtures of the enantiomers by separating thedesired enantiomer by using known techniques.

Compounds of this invention may also exhibit geometrical isomerism.Geometrical isomers include the cis and trans forms of compounds of theinvention having alkenyl or alkenylenyl moieties. The present inventioncomprises the individual geometrical isomers and stereoisomers andmixtures thereof.

C. Compound Preparation

The compounds of this invention can be prepared from readily availablestarting materials using the following general methods and procedures.Unless otherwise indicated, the starting materials are commerciallyavailable and well known in the art. It will be appreciated that wheretypical or preferred process conditions (i.e., reaction temperatures,times, mole ratios of reactants, solvents, pressures) are given, otherprocess conditions can also be used unless otherwise stated. Optimumreaction conditions may vary with the particular reactants or solventused, but such conditions can be determined by one skilled in the art byroutine optimization procedures.

Additionally, as will be apparent to those skilled in the art,conventional protecting groups may be necessary to prevent certainfunctional groups from undergoing undesired reactions. Suitableprotecting groups for various functional groups as well as suitableconditions for protecting and deprotecting particular functional groupsare well known in the art. For example, numerous protecting groups aredescribed in T. W. Greene and P. G. M. Wuts, Protecting Groups inOrganic Synthesis, Third Edition, Wiley, New York, 1999, and referencescited therein.

Furthermore, the compounds of this invention may contain one or morechiral centers. Accordingly, if desired, such compounds can be preparedor isolated as pure stereoisomers, i.e., as individual enantiomers ordiastereomers, or as stereoisomer-enriched mixtures. All suchstereoisomers (and enriched mixtures) are included within the scope ofthis invention, unless otherwise indicated. Pure stereoisomers (orenriched mixtures) may be prepared using, for example, optically activestarting materials or stereoselective reagents well-known in the art.Alternatively, racemic mixtures of such compounds can be separatedusing, for example, chiral column chromatography, chiral resolvingagents, and the like.

Compounds in the present invention may be better understood by thefollowing synthetic schemes that illustrate methods for the synthesis ofcompounds of the invention. Unless otherwise indicated, the reagentsused in the following examples are commercially available and may bepurchased from vendors such as Sigma-Aldrich Company, Inc. (Milwaukee,Wis., USA) or are known in the art. Benzimidazole compounds may besynthesized by Scheme 1 below:

Specifically, in Scheme 1, an appropriately substituted nitroaryl amine100 is combined with aldehyde 102 in a suitable solvent, such asdichloromethane under reductive amination conditions in the presence ofa suitable reducing agent such as sodium borohydride. The reaction isstirred at room temperature until complete. The resulting substitutedamine 104 can be recovered and optionally purified by conventionalmethods, such as precipitation, filtration, evaporation,crystallization, chromatography, and the like. Alternatively, thesubstituted amine 104 can be used in the next step without purificationor isolation.

Compounds of the invention when R⁵ is L-A¹ and L is —S(O)_(r)—, may besynthesized using a suitable sulfonyl chloride. Descriptions of varioussulfonyl chlorides may be found, for example, in U.S. Pat. No.6,489,300, which is hereby incorporated by reference.

The nitro group on the substituted amine 104 is then reduced using areducing agent, such as zinc or iron, under acidic conditions to providethe diamine 106. The resulting diamine 106 is then recovered andoptionally purified by conventional methods, such as precipitation,filtration, evaporation, crystallization, chromatography, and the like.Alternatively, the diamine 106 can be used in the next step withoutfurther purification or isolation.

The diamine is then coupled with a stoichiometric equivalent or a slightexcess of an appropriately amino protected (PG) α-amino acid 107 (notshown). The amino acid is preferably a known amino acid or can beprepared from known compounds by conventional synthetic procedures.Further, the amino acid selected may be in either (D) or (L)configuration or a racemic mixture to produce the appropriate (R) or (S)configuration or racemic mixture of compound 108. Coupling proceeds viaconventional amidation conditions well known in the art typically in thepresence of a suitable coupling agent, such as TBTU(N,N,N′,N′-tetramethyl-O-(benzotraizol-1-yl)uronium tetrafluoroborate).It should be noted that amino acid 107 is typically commerciallyavailable as are α,α-disubstituted amino acids (PG-NH—C(R¹)(R²)—COOH).Upon substantial completion of the reaction, typically 8 to 12 h, theresulting substituted diamine 108 can be recovered and optionallypurified by conventional methods, such as precipitation, filtration,evaporation, crystallization, chromatography, and the like.Alternatively, the substituted diamine 108 can be used in the next stepwithout purification or isolation.

Substituted diamine 108 is then treated under cyclization conditionswhich include, for example, heating a solution of the diamine for 2 to 4h at a temperature of from about 100 to about 110° C., under acidicconditions to provide the substituted arylimidazole 110. The reaction iscontinued until substantially complete to afford the substitutedarylimidazole 110. This product can be recovered and optionally purifiedby conventional methods, such as precipitation, filtration, evaporation,crystallization, chromatography, and the like. Alternatively, thesubstituted arylimidazole 110 can be used in the next step withoutpurification.

The protecting group of substituted arylimidazole 110 is removed byconventional techniques to provide amine 112. The amine 112 can then berecovered and optionally purified by conventional methods, such asprecipitation, filtration, evaporation, crystallization, chromatography,and the like.

Amine 112 is reacted under conventional reductive amination conditionsas described above with aldehyde 114 to provide for substituted amine116 which is then recovered and optionally purified by conventionalmethods such as precipitation, filtration, evaporation, crystallization,chromatography and the like. Alternatively, substituted amine 116 can beused directly in the next step without purification and/or isolation.

Substituted amine 116 is then reacted under conventional amidationconditions with an appropriate acyl chloride. Any protecting groups,such as PG′, remaining on the resulting amide product, 118 can beremoved by conventional procedures and the product can be recovered andpurified by conventional methods, such as precipitation, filtration,evaporation, crystallization, chromatography and the like.

Examples of commercially available 1-amino-2-nitroaryl and1-amino-2-nitro heteroaryl compounds include, for example,2-nitroaniline, 2-fluoro-5-nitroaniline, 4-fluoro-2-nitroaniline,2-chloro-5-nitroaniline, 4-chloro-2-nitroaniline,2-bromo-5-nitroaniline, 4-methyl-2-nitroaniline,4-amino-3-nitrobenzonitrile, 2-amino-3-nitropyridine, and the like.Derivation of such compounds into other starting materials useful inScheme 1 above is well within the skill of the art.

It will be well within the skill of the art to modify the abovepreparation to synthesize other imidazole compounds of the invention.

Indole compounds of this invention may be synthesized following scheme 2below:

Specifically in Scheme 2, an appropriately protected indole 144 iscombined with a slight excess of a suitable alkyl lithium, such asn-butyl lithium, in a suitable solvent such as tetrahydrofuran (THF).The protected indole 144 can be synthesized by protecting a commerciallyavailable indole with a protecting group under conventional means. Then,the mixture is warmed to effect anion formation (not shown) andsubsequently cooled. A solution of aldehyde 146 is added slowly. Theresulting alcohol is then oxidized to the corresponding ketone usingconventional means. Then, the protecting group is removed from thenitrogen using conventional means. The resulting ketone 152 is thenrecovered and optionally purified by conventional methods such asprecipitation, filtration, evaporation, crystallization, chromatographyand the like. Alternatively, ketone 152 can be used in the next stepwithout further purification and/or isolation.

Ketone 152 is then reacted with an appropriate aryl orheteroaryl-substituted alkyl halide 154, such as benzyl bromide.Typically, this can be accomplished by stirring the ketone 152 with anexcess of potassium hydroxide and DMF and then adding at least anequimolar amount of the aryl or heteroaryl-substituted alkyl halide 154.The resulting ketone 156 is then recovered and optionally purified usingconventional methods such as precipitation, filtration, evaporation,crystallization, chromatography and the like. Alternatively, ketone 156can be used in the next step without further purification and/orisolation.

If L is —S(O)_(r)— and r is two, then an appropriately substitutedsulfonyl chloride may be used in place of alkyl halide 154.

Ketone 156 is then reduced to the corresponding alcohol 158 byconventional reducing agents such as sodium borohydride underconventional conditions.

Amine 162 is prepared from alcohol 156 with an excess, e.g., about 3equivalents of a suitable amino protecting group, such as phthalimide.To the reaction is then added an excess of both triphenylphosphine anddiisopropyl diazodicarboxylate (DIAD) while maintaining the reaction ata temperature of from about −20 to about 10° C. The reaction is allowedto warm to room temperature and continued until it is substantiallycomplete, typically about 2 to about 24 h. The resulting protected amine(not shown) is then recovered and optionally purified by conventionalmethods such as precipitation, filtration, evaporation, crystallization,chromatography, and the like. Alternatively, the protected amine can beused directly in the next step without purification and/or isolation.

The protecting group is then removed by conventional techniques toprovide for amine 162, which is then recovered and optionally purifiedby conventional methods such as precipitation, filtration, evaporation,crystallization, chromatography and the like. Alternatively, amine 162can be used directly in the next step without purification and/orisolation.

Amine 162 is reacted under conventional reductive amination conditionsdescribed above with aldehyde 164 to provide for substituted amine 166which is then recovered and optionally purified by conventional methodssuch as precipitation, filtration, evaporation, crystallization,chromatography and the like. Alternatively, substituted amine 166 can beused directly in the next step without purification and/or isolation.

Substituted amine 166 is then reacted under conventional amidationconditions with acyl chloride 168. Any protecting groups remaining onthe resulting amide product can be removed by conventional methods andthe product can be recovered and purified by conventional methods suchas precipitation, filtration, evaporation, crystallization,chromatography and the like.

It will be well within the skill of the art to further modify the abovepreparation to synthesize other compounds of this invention.

D. Pharmaceutical Formulations

When employed as pharmaceuticals, the compounds of the subject inventionare usually administered in the form of pharmaceutical compositions.These compositions can be administered by a variety of routes includingoral, parenteral, transdermal, topical, rectal, and intranasal. Thesecompounds are effective, for example, as both injectable and oralcompositions. Such compositions are prepared in a manner well known inthe pharmaceutical art and comprise at least one active compound.

This invention also includes pharmaceutical compositions which contain,as the active ingredient, one or more of the compounds of the subjectinvention above associated with pharmaceutically acceptable carriers. Inmaking the compositions of this invention, the active ingredient isusually mixed with an excipient, diluted by an excipient or enclosedwithin such a carrier which can be in the form of a capsule, sachet,paper or other container. The excipient employed is typically anexcipient suitable for administration to human subjects or othermammals. When the excipient serves as a diluent, it can be a solid,semi-solid, or liquid material, which acts as a vehicle, carrier ormedium for the active ingredient. Thus, the compositions can be in theform of tablets, pills, powders, lozenges, sachets, cachets, elixirs,suspensions, emulsions, solutions, syrups, aerosols (as a solid or in aliquid medium), ointments containing, for example, up to 10% by weightof the active compound, soft and hard gelatin capsules, suppositories,sterile injectable solutions, and sterile packaged powders.

In preparing a formulation, it may be necessary to mill the activecompound to provide the appropriate particle size prior to combiningwith the other ingredients. If the active compound is substantiallyinsoluble, it ordinarily is milled to a particle size of less than 200mesh. If the active compound is substantially water soluble, theparticle size is normally adjusted by milling to provide a substantiallyuniform distribution in the formulation, e.g., about 40 mesh.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose. The formulations can additionally include: lubricating agentssuch as talc, magnesium stearate, and mineral oil; wetting agents;emulsifying and suspending agents; preserving agents such as methyl- andpropylhydroxy-benzoates; sweetening agents; and flavoring agents. Thecompositions of the invention can be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.

The quantity of active component, that is the compound according to thesubject invention, in the pharmaceutical composition and unit dosageform thereof may be varied or adjusted widely depending upon theparticular application, the potency of the particular compound and thedesired concentration.

The compositions are preferably formulated in a unit dosage form, eachdosage containing from about 1 to about 500 mg, usually about 5 to about100 mg, occasionally about 10 to about 30 mg, of the active ingredient.The term “unit dosage forms” refers to physically discrete unitssuitable as unitary dosages for human subjects and other mammals, eachunit containing a predetermined quantity of active material calculatedto produce the desired therapeutic effect, in association with asuitable pharmaceutical excipient. Preferably, the compound of thesubject invention above is employed at no more than about 20 weightpercent of the pharmaceutical composition, more preferably no more thanabout 15 weight percent, with the balance being pharmaceutically inertcarrier(s).

The active compound is effective over a wide dosage range and isgenerally administered in a pharmaceutically or therapeuticallyeffective amount. It will be understood, however, that the amount of thecompound actually administered will be determined by a physician, in thelight of the relevant circumstances, including the condition to betreated, the severity of the condition being treated, the chosen routeof administration, the actual compound administered, the age, weight,and response of the individual patient, the severity of the patient'ssymptoms, and the like.

In therapeutic use for treating, or combating, cancer in mammals, thecompounds or pharmaceutical compositions thereof will be administered byany appropriate route, such as orally, topically, transdermally, and/orparenterally at a dosage to obtain and maintain a concentration, thatis, an amount, or blood-level of active component in the mammalundergoing treatment that will be therapeutically effective. This isdiscussed in the next section in more detail.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present invention. When referring to thesepreformulation compositions as homogeneous, it is meant that the activeingredient is dispersed evenly throughout the composition so that thecomposition may be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules. This solid preformulation isthen subdivided into unit dosage forms of the type described abovecontaining from, for example, 0.1 to about 500 mg of the activeingredient of the present invention.

The tablets or pills of the present invention may be coated or otherwisecompounded to provide a dosage form affording the advantage of prolongedaction. For example, the tablet or pill can comprise an inner dosage andan outer dosage component, the latter being in the form of an envelopeover the former. The two components can be separated by an enteric layerwhich serves to resist disintegration in the stomach and permit theinner component to pass intact into the duodenum or to be delayed inrelease. A variety of materials can be used for such enteric layers orcoatings, such materials including a number of polymeric acids andmixtures of polymeric acids with such materials as shellac, cetylalcohol, and cellulose acetate.

The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavored syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as corn oil,cottonseed oil, sesame oil, coconut oil, or peanut oil, as well aselixirs and similar pharmaceutical vehicles.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. Preferably the compositions are administered by the oral or nasalrespiratory route for local or systemic effect. Compositions inpreferably pharmaceutically acceptable solvents may be nebulized by useof inert gases. Nebulized solutions may be inhaled directly from thenebulizing device or the nebulizing device may be attached to a facemask tent, or intermittent positive pressure breathing machine.Solution, suspension, or powder compositions may be administered,preferably orally or nasally, from devices which deliver the formulationin an appropriate manner.

The following formulation examples illustrate representativepharmaceutical compositions of the present invention.

FORMULATION EXAMPLE 1

Hard gelatin capsules containing the following ingredients are prepared:Quantity Ingredient (mg/capsule) Active Ingredient 30.0 Starch 305.0Magnesium stearate 5.0

The above ingredients are mixed and filled into hard gelatin capsules in340 mg quantities.

FORMULATION EXAMPLE 2

A tablet formula is prepared using the ingredients below: QuantityIngredient (mg/tablet) Active Ingredient 25.0 Cellulose,microcrystalline 200.0 Colloidal silicon dioxide 10.0 Stearic acid 5.0

The components are blended and compressed to form tablets, each weighing240 mg.

FORMULATION EXAMPLE 3

A dry powder inhaler formulation is prepared containing the followingcomponents: Ingredient Weight % Active Ingredient 5 Lactose 95

The active ingredient is mixed with the lactose and the mixture is addedto a dry powder inhaling appliance.

FORMULATION EXAMPLE 4

Tablets, each containing 30 mg of active ingredient, are prepared asfollows Quantity Ingredient (mg/tablet) Active Ingredient 30.0 mg Starch45.0 mg Microcrystalline cellulose 35.0 mg Polyvinylpyrrolidone  4.0 mg(as 10% solution in sterile water) Sodium carboxymethyl starch  4.5 mgMagnesium stearate  0.5 mg Talc  1.0 mg Total  120 mg

The active ingredient, starch and cellulose are passed through a No. 20mesh U.S. sieve and mixed thoroughly. The solution ofpolyvinylpyrrolidone is mixed with the resultant powders, which are thenpassed through a 16 mesh U.S. sieve. The granules so produced are driedat 50° C. to 60° C. and passed through a 16 mesh U.S. sieve. The sodiumcarboxymethyl starch, magnesium stearate, and talc, previously passedthrough a No. 30 mesh U.S. sieve, are then added to the granules which,after mixing, are compressed on a tablet machine to yield tablets eachweighing 120 mg.

FORMULATION EXAMPLE 5

Capsules, each containing 40 mg of medicament are made as follows:Quantity Ingredient (mg/capsule) Active Ingredient  40.0 mg Starch 109.0mg Magnesium stearate  1.0 mg Total 150.0 mg

The active ingredient, starch and magnesium stearate are blended, passedthrough a No. 20 mesh U.S. sieve, and filled into hard gelatin capsulesin 150 mg quantities.

FORMULATION EXAMPLE 6

Suppositories, each containing 25 mg of active ingredient are made asfollows: Ingredient Amount Active Ingredient   25 mg Saturated fattyacid glycerides to 2,000 mg

The active ingredient is passed through a No. 60 mesh U.S. sieve andsuspended in the saturated fatty acid glycerides previously melted usingthe minimum heat necessary. The mixture is then poured into asuppository mold of nominal 2.0 g capacity and allowed to cool.

FORMULATION EXAMPLE 7

Suspensions, each containing 50 mg of medicament per 5.0 mL dose aremade as follows: Ingredient Amount Active Ingredient 50.0 mg Xanthan gum4.0 mg Sodium carboxymethyl cellulose (11%) 50.0 mg Microcrystallinecellulose (89%) Sucrose 1.75 g Sodium benzoate 10.0 mg Flavor and Colorq.v. Purified water to 5.0 mL

The active ingredient, sucrose and xanthan gum are blended, passedthrough a No. 10 mesh U.S. sieve, and then mixed with a previously madesolution of the microcrystalline cellulose and sodium carboxymethylcellulose in water. The sodium benzoate, flavor, and color are dilutedwith some of the water and added with stirring. Sufficient water is thenadded to produce the required volume.

FORMULATION EXAMPLE 8

Quantity Ingredient (mg/capsule) Active Ingredient  15.0 mg Starch 407.0mg Magnesium stearate  3.0 mg Total 425.0 mg

The active ingredient, starch, and magnesium stearate are blended,passed through a No. 20 mesh U.S. sieve, and filled into hard gelatincapsules in 425.0 mg quantities.

FORMULATION EXAMPLE 9

A subcutaneous formulation may be prepared as follows: IngredientQuantity Active Ingredient 5.0 mg Corn Oil 1.0 mL

FORMULATION EXAMPLE 10

A topical formulation may be prepared as follows: Ingredient QuantityActive Ingredient 1-10 g Emulsifying Wax 30 g Liquid Paraffin 20 g WhiteSoft Paraffin to 100 g

The white soft paraffin is heated until molten. The liquid paraffin andemulsifying wax are incorporated and stirred until dissolved. The activeingredient is added and stirring is continued until dispersed. Themixture is then cooled until solid.

FORMULATION EXAMPLE 11

An intravenous formulation may be prepared as follows: IngredientQuantity Active Ingredient  250 mg Isotonic saline 1000 mL

Another preferred formulation employed in the methods of the presentinvention employs transdermal delivery devices (“patches”). Suchtransdermal patches may be used to provide continuous or discontinuousinfusion of the compounds of the present invention in controlledamounts. The construction and use of transdermal patches for thedelivery of pharmaceutical agents is well known in the art. See, e.g.,U.S. Pat. No. 5,023,252, issued Jun. 11, 1991, herein incorporated byreference. Such patches may be constructed for continuous, pulsatile, oron demand delivery of pharmaceutical agents.

Frequently, it will be desirable or necessary to introduce thepharmaceutical composition to the brain, either directly or indirectly.Direct techniques usually involve placement of a drug delivery catheterinto the host's ventricular system to bypass the blood-brain barrier.One such implantable delivery system used for the transport ofbiological factors to specific anatomical regions of the body isdescribed in U.S. Pat. No. 5,011,472 which is herein incorporated byreference.

Indirect techniques, which are generally preferred, usually involveformulating the compositions to provide for drug latentiation by theconversion of hydrophilic drugs into lipid-soluble drugs. Latentiationis generally achieved through blocking of the hydroxy, carbonyl,sulfate, and primary amine groups present on the drug to render the drugmore lipid soluble and amenable to transportation across the blood-brainbarrier. Alternatively, the delivery of hydrophilic drugs may beenhanced by intra-arterial infusion of hypertonic solutions which cantransiently open the blood-brain barrier.

Other suitable formulations for use in the present invention can befound in Remington's Pharmaceutical Sciences, Mack Publishing Company,Philadelphia, Pa., 17th ed. (1985).

E. Dosage and Administration

As noted above, the compounds described herein are suitable for use in avariety of drug delivery systems described above. Additionally, in orderto enhance the in vivo serum half-life of the administered compound, thecompounds may be encapsulated, introduced into the lumen of liposomes,prepared as a colloid, or other conventional techniques may be employedwhich provide an extended serum half-life of the compounds. A variety ofmethods are available for preparing liposomes, as described in, e.g.,Szoka, et al., U.S. Pat. Nos. 4,235,871, 4,501,728 and 4,837,028 each ofwhich is incorporated herein by reference.

Compounds of the instant invention are useful for inhibiting or treatinga disorder mediated, at least in part, by the activity of KSP. In oneaspect, the disorder that is mediated, at least in part by KSP, is acellular proliferative disorder. The term “cellular proliferativedisorder” or “cell proliferative disorder” refers to diseases including,for example, cancer, tumor, hyperplasia, restenosis, cardiachypertrophy, immune disorder and inflammation. The present inventionprovides methods of treating a human or mammalian subject in need ofsuch treatment, comprising administering to the subject atherapeutically effective amount of a compound of formula I or II,either alone or in combination with other anticancer agents.

The compounds of the invention are useful in vitro or in vivo ininhibiting the growth of cancer cells. The term “cancer” refers tocancer diseases including, for example, lung and bronchus; prostate;breast; pancreas; colon and rectum; thyroid; stomach; liver andintrahepatic bile duct; kidney and renal pelvis; urinary bladder;uterine corpus; uterine cervix; ovary; multiple myeloma; esophagus;acute myelogenous leukemia; chronic myelognous leukemia; lymphocyticleukemia; myeloid leukemia; brain; oral cavity and pharynx; larynx;small intestine; non-hodgkin lymphoma; melanoma; and villous colonadenoma.

Cancer also includes tumors or neoplasms selected from the groupconsisting of carcinomas, adenocarcinomas, sarcomas, and hematologicalmalignancies.

Additionally, the type of cancer can be selected from the groupconsisting of growth of solid tumors/malignancies, myxoid and round cellcarcinoma, locally advanced tumors, human soft tissue carcinoma, cancermetastases, squamous cell carcinoma, esophageal squamous cell carcinoma,oral carcinoma, cutaneous T cell lymphoma, Hodgkin's lymphoma,non-Hodgkin's lymphoma, cancer of the adrenal cortex, ACTH-producingtumors, nonsmall cell cancers, breast cancer, gastrointestinal cancers,urological cancers, malignancies of the female genital tract,malignancies of the male genital tract, kidney cancer, brain cancer,bone cancers, skin cancers, thyroid cancer, retinoblastoma,neuroblastoma, peritoneal effusion, malignant pleural effusion,mesothelioma, Wilms's tumors, gall bladder cancer, trophoblasticneoplasms, hemangiopericytoma, and Kaposi's sarcoma.

A compound or composition of this invention may be administered to amammal by a suitable route, such as orally, intravenously, parenterally,transdermally, topically, rectally, or intranasally.

Mammals include, for example, humans and other primates, pet orcompanion animals, such as dogs and cats, laboratory animals, such asrats, mice and rabbits, and farm animals, such as horses, pigs, sheep,and cattle.

Tumors or neoplasms include growths of tissue cells in which themultiplication of the cells is uncontrolled and progressive. Some suchgrowths are benign, but others are termed “malignant” and can lead todeath of the organism. Malignant neoplasms or “cancers” aredistinguished from benign growths in that, in addition to exhibitingaggressive cellular proliferation, they can invade surrounding tissuesand metastasize. Moreover, malignant neoplasms are characterized in thatthey show a greater loss of differentiation (greater“dedifferentiation”) and organization relative to one another and tosurrounding tissues. This property is called “anaplasia.”

Compounds having the desired biological activity may be modified asnecessary to provide desired properties such as improved pharmacologicalproperties (e.g., in vivo stability, bio-availability), or the abilityto be detected in diagnostic applications. Stability can be assayed in avariety of ways such as by measuring the half-life of the compoundsduring incubation with peptidases or human plasma or serum.

For diagnostic purposes, a wide variety of labels may be linked to thecompounds, which may provide, directly or indirectly, a detectablesignal. Thus, the compounds and/or compositions of the subject inventionmay be modified in a variety of ways for a variety of end purposes whilestill retaining biological activity. In addition, various reactive sitesmay be introduced for linking to particles, solid substrates,macromolecules, and the like.

Labeled compounds can be used in a variety of in vivo or in vitroapplications. A wide variety of labels may be employed, such asradionuclides (e.g., gamma-emitting radioisotopes such as technetium-99or indium-111), fluorescers (e.g., fluorescein), enzymes, enzymesubstrates, enzyme cofactors, enzyme inhibitors, chemiluminescentcompounds, bioluminescent compounds, and the like. Those of ordinaryskill in the art will know of other suitable labels for binding to thecomplexes, or will be able to ascertain such using routineexperimentation. The binding of these labels is achieved using standardtechniques common to those of ordinary skill in the art.

Pharmaceutical compositions of the invention are suitable for use in avariety of drug delivery systems. Suitable formulations for use in thepresent invention are found in Remington's Pharmaceutical Sciences, MacePublishing Company, Philadelphia, Pa., 17th ed. (1985).

The amount administered to the patient will vary depending upon what isbeing administered, the purpose of the administration, such asprophylaxis or therapy, the state of the patient, the manner ofadministration, and the like. In therapeutic applications, compositionsare administered to a patient already suffering from a disease in anamount sufficient to cure or at least partially arrest the progressionor symptoms of the disease and its complications. An amount adequate toaccomplish this is defined as “therapeutically effective dose.” Amountseffective for this use will depend on the disease condition beingtreated as well as by the judgment of the attending clinician dependingupon factors such as the severity of the disease, disorder or condition,the age, weight and general condition of the patient, and the like.

The compounds administered to a patient are typically in the form ofpharmaceutical compositions described above. These compositions may besterilized by conventional sterilization techniques, or may be sterilefiltered. The resulting aqueous solutions may be packaged for use as is,or lyophilized, the lyophilized preparation being combined with asterile aqueous carrier prior to administration. The pH of the compoundpreparations typically will be between about 3 and 11, more preferablyfrom about 5 to 9 and most preferably from about 7 to 8. It will beunderstood that use of certain of the foregoing excipients, carriers, orstabilizers will result in the formation of pharmaceutical salts.

The therapeutic dosage of the compounds and/or compositions of thepresent invention will vary according to, for example, the particularuse for which the treatment is made, the manner of administration of thecompound, the health and condition of the patient, and the judgment ofthe prescribing physician. For example, for oral administration, thedose will typically be in the range of about 5 μg to about 50 mg perkilogram body weight per day, preferably about 1 mg to about 10 mg perkilogram body weight per day. In the alternative, for intravenousadministration, the dose will typically be in the range of about 5 μg toabout 50 mg per kilogram body weight, preferably about 500 μg to about5000 μg per kilogram body weight. Alternative routes of administrationcontemplated include, but are not limited to, intranasal, transdermal,inhaled, subcutaneous and intramuscular. Effective doses can beextrapolated from dose-response curves derived from in vitro or animalmodel test systems.

In general, the compounds and/or compositions of the subject inventionwill be administered in a therapeutically effective amount by any of theaccepted modes of administration for agents that serve similarutilities. Toxicity and therapeutic efficacy of such compounds can bedetermined by standard pharmaceutical procedures in cell cultures orexperimental animals, e.g., for determining the LD₅₀ (the dose lethal to50% of the population) and the ED₅₀ (the dose therapeutically effectivein 50% of the population). The dose ratio between toxic and therapeuticeffects is the therapeutic index and it can be expressed as the ratioLD₅₀/ED₅₀. Compounds that exhibit large therapeutic indices arepreferred.

The data obtained from the cell culture assays and animal studies can beused in formulating a range of dosage for use in humans. The dosage ofsuch compounds lies preferably within a range of circulatingconcentrations that include the ED₅₀ with little or no toxicity. Thedosage may vary within this range depending upon the dosage formemployed and the route of administration utilized. For any compoundand/or composition used in the method of the invention, thetherapeutically effective dose can be estimated initially from cellculture assays. A dose may be formulated in animal models to achieve acirculating plasma concentration range which includes the IC₅₀ (theconcentration of the test compound which achieves a half-maximalinhibition of activity) as determined in cell culture. Such informationcan be used to more accurately determine useful doses in humans. Levelsin plasma may be measured, for example, by high performance liquidchromatography.

The following synthetic and biological examples are offered toillustrate this invention and are not to be construed in any way aslimiting the scope of this invention.

EXAMPLES

Referring to the examples that follow, compounds of the presentinvention were synthesized using the methods described herein, or othermethods, which are well known in the art.

The compounds and/or intermediates were characterized by highperformance liquid chromatography (HPLC) using a Waters Milleniumchromatography system with a 2690 Separation Module (Milford, Mass.).The analytical columns were Alltima C-18 reversed phase, 4.6×250 mm fromAlltech (Deerfield, Ill.). A gradient elution was used, typicallystarting with 5% acetonitrile/95% water and progressing to 100%acetonitrile over a period of 40 minutes. All solvents contained 0.1%trifluoroacetic acid (TFA). Compounds were detected by ultraviolet light(UV) absorption at either 220 or 254 nm. HPLC solvents were from Burdickand Jackson (Muskegan, Mich.), or Fisher Scientific (Pittsburgh, Pa.).In some instances, purity was assessed by thin layer chromatography(TLC) using glass or plastic backed silica gel plates, such as, forexample, Baker-Flex Silica Gel 1B2-F flexible sheets. TLC results werereadily detected visually under ultraviolet light, or by employing wellknown iodine vapor and other various staining techniques.

Mass spectrometric analysis was performed on one of two LC/MSinstruments: a Waters System (Alliance HT HPLC and a Micromass ZQ massspectrometer; Column: Eclipse XDB-C18, 2.1×50 mm; solvent system: 5-95%(or 35-95%, or 65-95% or 95-95%) acetonitrile in water with 0.05% TFA;flow rate 0.8 mL/min; molecular weight range 500-1500; cone Voltage 20V; column temperature 40° C.) or a Hewlett Packard System (Series 1100HPLC; Column: Eclipse XDB-C18, 2.1×50 mm; solvent system: 1-95%acetonitrile in water with 0.05% TFA; flow rate 0.4 mL/min; molecularweight range 150-850; cone Voltage 50 V; column temperature 30° C.). Allmasses were reported as those of the protonated parent ions.

GC/MS analysis is performed on a Hewlett Packard instrument (HP6890Series gas chromatograph with a Mass Selective Detector 5973; injectorvolume: 1 mL; initial column temperature: 50° C.; final columntemperature: 250° C.; ramp time: 20 minutes; gas flow rate: 1 mL/min;column: 5% phenyl methyl siloxane, Model No. HP 190915-443, dimensions:30.0 m×25 m×0.25 m).

Nuclear magnetic resonance (NMR) analysis was performed on some of thecompounds with a Varian 300 MHz NMR (Palo Alto, Calif.). The spectralreference was either TMS or the known chemical shift of the solvent.Some compound samples were run at elevated temperatures (e.g., 75° C.)to promote increased sample solubility.

The purity of some of the invention compounds is assessed by elementalanalysis (Desert Analytics, Tucson, Ariz.).

Melting points are determined on a Laboratory Devices Mel-Temp apparatus(Holliston, Mass.).

Preparative separations were carried out using a Flash 40 chromatographysystem and KP-Sil, 60A (Biotage, Charlottesville, Va.), or by flashcolumn chromatography using silica gel (230-400 mesh) packing material,or by HPLC using a C-18 reversed phase column. Typical solvents employedfor the Flash 40 Biotage system and flash column chromatography weredichloromethane, methanol, EtOAc, hexane, acetone, aqueous hydroxyamineand triethyl amine. Typical solvents employed for the reverse phase HPLCwere varying concentrations of acetonitrile and water with 0.1%trifluoroacetic acid.

Unless otherwise stated all temperatures are in degrees Celsius. Also,in these examples and elsewhere, abbreviations have the followingmeanings:

Unless otherwise stated all temperatures are in degrees Celsius. Also,in these examples and elsewhere, abbreviations have the followingmeanings:

aq.=aqueous

ATP=adenosine triphosphate

boc=t-butoxy carbonyl

BSA=bovine serum albumin

DCM=dichloromethane

DIAD=diisopropyl diazodicarboxylate

DMAP=dimethylaminopyridine

DME=dimethoxy ethane

DMF=dimethylformamide

DMSO=dimethylsulfoxide

DTT=dithiothreitol

eq.=equivalence

Et₃N=triethyl amine

EtOAc=ethyl acetate

EtOH=ethanol

g=gram

h=hour

HPLC=high performance liquid chromatography

L=liter

M=molar

MeOH=methanol

mg=milligram

min=minute

mL=milliliter

mM=millimolar

mmol=millimole

mol=mole

N=normal

nm=nanometer

Ph=phenyl

Ph₃P=triphenyl phosphine

TBTU=N,N,N′,N′-tetramethyl-O-(benzotraizol-1-yl)uroniumtetrafluoroborate

THF=tetrahydrofuran

TMS=trimethyl silyl

μg=micrograms

μl=microliter

μM=micromolar

Example 1N-(3-Amino-propyl)-N-[1-(1-benzyl-5-methyl-1H-benzimidazol-2-yl)-2-methyl-propyl]-4-methyl-benzamide(compound 3) Step 1. Benzyl-(4-methyl-2-nitro-phenyl)-amine

To a solution of 4-methyl-2-nitro-phenylamine (202 mg, 1.33 mmol) andbenzaldehyde (0.68 mL, 6.65 mmol) in 5 mL dry dichloromethane at roomtemperature, was added sodium triacetoxyborohydride (282 mg, 1.33 mmol).Then acetic acid (76 μl, 1.33 mmol) was added. The reaction mixture wasstirred at room temperature for 1 h. The solvent was evaporated and thesolid was dissolved in ethyl acetate. The organic layer was washed withsaturated NaHCO₃, dried over MgSO₄, filtered, and the solvent wasremoved in vacuo. The crude material was purified by flashchromatography to yield 300 mg (1.24 mmol, 94%) ofbenzyl-(4-methyl-2-nitro-phenyl)-amine.

Step 2. N1-Benzyl-4-methyl-benzene-1,2-diamine

To a solution of benzyl-(4-methyl-2-nitro-phenyl)-amine (300 mg, 1.24mmol) in 5 mL acetic acid, was added iron (300 mg, 1.24 mmol). Thereaction mixture was heated to 40° C. under argon for 2 h. The mixturewas cooled to ambient temperature and filtered through celite and thefiltrate was concentrated. The resulting solid was dissolved in ethylacetate. The organic layer was washed with saturated NaHCO₃, dried overMgSO₄, filtered and the filtrate was concentrated in vacuo to yieldcrude product that was used in step 3.

Step 3.[1-(2-Benzylamino-5-methyl-phenylcarbamoyl)-2-methyl-propyl]-carbamicacid tert-butyl ester

To a solution of N1-benzyl-4-methyl-benzene-1,2-diamine (1.24 mmol) andtriethylamine (0.26 mL, 1.86 mmol) in dry DMF (5 mL), was addedboc-D-valine (296 mg, 1.36 mmol) followed by TBTU (400 mg, 1.24 mmol).The reaction mixture was stirred at room temperature overnight. Ethylacetate was added. The organic layer was washed with saturated NaHCO₃,dried over MgSO₄, filtered, and the filtrated was concentrated in vacuo.The crude material was purified by flash chromatography to yield[1-(2-Benzylamino-5-methyl-phenylcarbamoyl)-2-methyl-propyl]-carbamicacid tert-butyl ester.

Step 4.[1-(1-Benzyl-5-methyl-1H-benzimidazol-2-yl)-2-methyl-propyl]-carbamicacid tert-butyl ester

A solution of[1-(2-benzylamino-5-methyl-phenylcarbamoyl)-2-methyl-propyl]-carbamicacid tert-butyl ester (400 mg, 0.97 mmol) in acetic acid (4 mL) washeated at 100° C. for 2 h. The solvent was removed in vacuo and theresulting solid was dissolved in ethyl acetate. The organic layer waswashed with saturated NaHCO₃, dried over MgSO₄, filtered and thefiltrate was concentrated in vacuo. The crude product was purified byflash chromatography to give of[1-(1-benzyl-5-methyl-1H-benzimidazol-2-yl)-2-methyl-propyl]-carbamicacid tert-butyl ester (300 mg).

Step 5. 1-(1-Benzyl-5-methyl-1H-benzimidazol-2-yl)-2-methyl-propylamine

To a solution of1-(1-benzyl-5-methyl-1H-benzimidazol-2-yl)-2-methyl-propylamine in DCM(2 mL), was added trifluoroacetic acid (0.5 mL). The reaction mixturewas stirred at room temperature for 30 min. The solvent was removed invacuo to give the free amine product.

Step 6a. 3-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-propionaldehyde

The reaction was carried out with oven dried glassware. DMSO (85 μl, 1.1mmol) was added to oxalyl chloride solution (0.35 mL 2 M DCM solutionwith 5 mL dry DCM) at −78° C. The reaction mixture was stirred at −78°C. for 10 min. 2-(3-Hydroxy-propyl)-isoindole-1,3-dione solution (102mg, 0.5 mmol, in 2 mL DCM) was added drop wise in 2 min. Thentriethylamine (0.35 mL, 2.5 mmol) was added drop wise in 2 min. Themixture was stirred for additional 30 minutes at −78° C. and was warmedup to room temperature. The reaction mixture was extracted with ethylacetate. The organic layer was washed with saturated sodium bicarbonate,dried over MgSO₄, filtered, and the filtrated was concentrated in vacuo.The crude product was purified by flash chromatography to give3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propionaldehyde.

Step 6b.2-{3-[1-(1-Benzyl-5-methyl-1H-benzimidazol-2-yl)-2-methyl-propylamino]-propyl}-isoindole-1,3-dione

To a solution of1-(1-benzyl-5-methyl-1H-benzimidazol-2-yl)-2-methyl-propylamine (0.56mmol) and 3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propionaldehyde (114mg, 0.56 mmol) in dry DCM (3 mL) at room temperature, was added sodiumtriacetoxyborohydride (119 mg, 0.56 mmol). After 10 min., acetic acid(34 μl, 0.56 mmol) was added to the reaction mixture. The mixture wasstirred at room temperature for 1 h. The solvent was removed in vacuoand the solid was dissolved in ethyl acetate. The organic layer waswashed with saturated NaHCO₃, dried over MgSO₄, filtered and thefiltrate was concentrated in vacuo. The crude product was purified byflash chromatography to give crude material that was used in step 7.

Step 7.N-[1-(1-Benzyl-5-methyl-1H-benzimidazol-2-yl)-2-methyl-propyl]-N-[3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propyl]-4-methyl-benzamide

To a solution of2-{3-[1-(1-benzyl-5-methyl-1H-benzimidazol-2-yl)-2-methyl-propylamino]-propyl}-isoindole-1,3-dione(0.56 mmol) and triethylamine (0.58 mL, 3.36 mmol) in DCM (3 mL) at 0°C., was added p-toluoyl chloride (0.38 mL, 2.8 mmol). The reactionmixture was stirred at 0° C. for 30 min. Ethyl acetate and saturatedsodium bicarbonate were added. The mixture was extracted with ethylacetate. The organic layers was combined, dried over MgSO₄, filtered,and the filtrate was concentrated in vacuo. The crude material waspurified by flash chromatography to giveN-[1-(1-benzyl-5-methyl-1H-benzimidazol-2-yl)-2-methyl-propyl]-N-[3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propyl]-4-methyl-benzamide(181 mg).

Step 8.N-(3-Amino-propyl)-N-[1-(1-benzyl-5-methyl-1H-benzimidazol-2-yl)-2-methyl-propyl]-4-methyl-benzamide

To a solution ofN-[1-(1-benzyl-5-methyl-1H-benzimidazol-2-yl)-2-methyl-propyl]-N-[3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propyl]-4-methyl-benzamide(0.302 mmol) in ethanol at room temperature, was added hydrazine (0.19mL, 6 mmol). The reaction was stirred at room temperature for 1 h. Thecrude product was purified via reverse phase chromatography to giveN-(3-amino-propyl)-N-[1-(1-benzyl-5-methyl-1H-benzimidazol-2-yl)-2-methyl-propyl]-4-methyl-benzamide(129 mg).

Example 2N-(3-Amino-propyl)-N-[1-(1-benzyl-5-vinyl-1H-benzimidazol-2-yl)-2-methyl-propyl]-4-methyl-benzamide

Step 1.[1-(1-Benzyl-5-vinyl-1H-benzimidazol-2-yl)-2-methyl-propyl]-carbamicacid tert-butyl ester

To a solution of[1-(1-benzyl-5-bromo-1H-benzimidazol-2-yl)-2-methyl-propyl]-carbamicacid tert-butyl ester (this compound was obtained starting from4-bromo-2-nitro-phenylamine following steps 1-4 in Example 1) (58 mg,0.127 mmol) in DME (2 mL) solution, was addedtetrakis(triphenylphosphine)palladium(0) (9 mg, 0.008 mmol). The mixturewas stirred at room temperature under argon for 10 min. Then potassiumcarbonate (18 mg, 0.127 mmol), water (0.6 mL) and2,4,6-trivinyl-cyclotriboroxane pyridine complex (48 mg, 0.127 mmol) wasadded to the reaction mixture. The mixture was heated at 110° C. underargon for 1 h and then was cooled down to room temperature. Ethylacetate and saturated sodium bicarbonate solution were added. Themixture was extracted with ethyl acetate. The organic layers was driedover MgSO₄, filtered, and the solvent was removed in vacuo. The residuewas subjected to flash chromatograph to give[1-(1-benzyl-5-vinyl-1H-benzimidazol-2-yl)-2-methyl-propyl]-carbamicacid tert-butyl ester (43 mg).

N-(3-Amino-propyl)-N-[1-(1-benzyl-5-vinyl-1H-benzimidazol-2-yl)-2-methyl-propyl]-4-methyl-benzamidewas synthesized from the preceding compound following the step 5 to step8 in Example 1, using methylhydrazine instead of hydrazine.

Example 3N-(3-Amino-propyl)-N-[1-(1-benzyl-5-ethynyl-1H-benzimidazol-2-yl)-2-methyl-propyl]-4-methyl-benzamide(Compound 22)

Step 1.[1-(1-Benzyl-5-trimethylsilanylethynyl-1H-benzimidazol-2-yl)-2-methyl-propyl]-carbamicacid tert-butyl ester

To a solution of[1-(1-benzyl-5-bromo-1H-benzimidazol-2-yl)-2-methyl-propyl]-carbamicacid tert-butyl ester (this compound was obtained starting from4-bromo-2-nitro-phenylamine following steps 1-4 in Example 1) (48 mg,0.105 mmol) in dioxane (3 mL) in a microwave reaction tube, was addedtetrakis(triphenylphosphine)palladium(0) (12 mg, 0.01 mmol), copper (I)iodide (2 mg, 0.01 mmol), ethynyl-trimethyl-silane (22 μl, 0.16 mmol),and triethylamine (0.4 mL). The mixture was purged argon for 5 min. andthen heated to 120° C. in microwave reactor for 10 min. The reaction wascooled down to room temperature. Ethyl acetate and saturated sodiumbicarbonate were added. The mixture was extracted with ethyl acetate.The organic layer was dried over MgSO₄, filtered, and the solvent wasremoved in vacuo. The residue was subjected to flash chromatograph togive[1-(1-benzyl-5-trimethylsilanylethynyl-1H-benzimidazol-2-yl)-2-methyl-propyl]-carbamicacid tert-butyl ester (20 mg).

Step 2.[1-(1-Benzyl-5-ethynyl-1H-benzimidazol-2-yl)-2-methyl-propyl]-carbamicacid tert-butyl ester

To a solution of[1-(1-benzyl-5-trimethylsilanylethynyl-1H-benzimidazol-2-yl)-2-methyl-propyl]-carbamicacid tert-butyl ester (20 mg, 0.042 mmol) in 2 mL THF at roomtemperature, was added 0.2 mL tetrabutylammonium fluoride solution (0.2mL of 1 N in THF solution). The reaction mixture was stirred at roomtemperature for 15 min. The solvent was removed under vacuum and theresidue was dissolved in a mixture of ethyl acetate and saturated sodiumbicarbonate. The mixture was extracted with ethyl acetate. The organiclayers was dried over MgSO₄, filtered, and the solvent was removed invacuo. The crude was used in next synthesis directly.

N-(3-Amino-propyl)-N-[1-(1-benzyl-5-ethynyl-1H-benzimidazol-2-yl)-2-methyl-propyl]-4-methyl-benzamidewas synthesized using the preceding compound following the step 5 tostep 8 in Example 1, using methylhydrazine instead of hydrazine.

Example 4N-(3-aminopropyl)-N-[1-(1-benzyl-5-chloro-1H-indol-2-yl)-2-methylpropyl]benzamide(Compound 45) Step 1. 1-phenylsulfonyl-5-chloroindole

To a stirred solution of 5-chloroindole (20 g, 131.93 mmol, 1 eq.) indry DMF (250 mL) at 0° C., was added NaH (5.38 g, 134.57 mmol, 1.02eq.). After stirring at room temperature for 1 h, benzenesulfonylchloride (23.77 g, 134.57 mmol, 1.02 eq.) was added slowly. The reactionmixture was stirred for additional 1 h, then poured into 1 L of 5% aq.NaHCO₃ and extracted with EtOAc (×3). The organic layers were combined,washed with H₂O (×3), brine (×3), dried over (Na₂SO₄), filtered, and thefiltrate was concentrated. The material was purified by flashchromatography to yield 30 g of 1-phenylsulfonyl-5-chloroindole ascolorless crystals.

Step 2. 1-(5-chloro-1-phenylsulfonylindole)-2-methylpropan-1-ol

To a solution of 1-phenylsulfonyl-5-chloroindole (6.8 mmol) in dry THF(20 mL) at −78° C., was added n-butyl lithium (10.2 mmol) drop wise(about 30 min). After stirring for 10 min., the mixture was warmed up to−20° C. It was then cooled to −78° C., a solution of isobutylaldehyde(10.2 mmol) in 5 mL of dry THF was added slowly. After warming up toroom temperature overnight, the mixture was poured into water, thenextracted with EtOAc (×3). The organic layers were combined, washed withH₂O (×3), brine (×3), dried over (Na₂SO₄), filtered, and the filtratewas concentrated. The material was purified by flash chromatography (20%EtOAc:hexane) to yield 2.4 g of1-(5-chloro-1-phenylsulfonylindole)-2-methylpropan-1-ol.

Step 3. 1-(5-Chloro-1-phenylsulfonylindole)-2-methylpropan-1-one

To a solution of 1-(5-chloro-1-phenylsulfonylindole)-2-methylpropan-1-ol(700 mg) in 35 mL of chloroform was added MnO₂ (6.7 g). The mixture wasstirred at room temperature overnight, filtered over celite and thefiltrate was concentrated. The crude material was purified by flashchromatography (30% EtOAc:hexane) to yield1-(5-chloro-1-phenylsulfonylindole)-2-methylpropan-1-one as colorlessoil.

Step 4. 1-(5-chloro-1H-indole-2-yl)-2-methylpropan-1-one

To a solution of ethanol (20 mL) and 10% aq. NaOH (10 mL), was added1-(5-chloro-1-phenylsulfonylindole)-2-methylpropan-1-one (290 mg). Themixture was heated under reflux for 2 h. After cooling, the solution waspoured into water, and extracted with EtOAc (×3). The organic layerswere combined, washed with H₂O (×3), brine (×3), dried over (Na₂SO₄),filtered, and the filtrate was concentrated to give 227 mg of1-(5-chloro-1H-indole-2-yl)-2-methylpropan-1-one.

Step 5. 1-(1-benzyl-5-chloro-1H-indole-2-yl)-2-methylpropan-1-one

To a solution of 1-(5-chloro-1H-indole-2-yl)-2-methylpropan-1-one (1mmol) in 15 mL of DMF, was added KOH (2 mmol) at 0° C. The mixture wasstirred for 30 min., followed by adding benzyl bromide (2 mmol) slowly.The mixture was warmed up to room temperature and stirred for additional1 h. The solution was poured into water, and extracted with EtOAc (×3).The organic layers were combined, washed with H₂O (×3), brine (×3),dried (Na₂SO₄), filtered, and the filtrate was concentrated. Thematerial was purified by flash chromatography (10% EtOAc:hexane) toyield 1-(1-benzyl-5-chloro-1H-indole-2-yl)-2-methylpropan-1-one.

Step 6. 1-(1-benzyl-5-chloro-1H-indole-2-yl)-2-methylpropan-1-ol

To a solution of1-(1-benzyl-5-chloro-1H-indole-2-yl)-2-methylpropan-1-one (0.6 mmol) in5 mL of MeOH, was added NaBH₄ (1.8 mmol) at 0° C. The mixture wasstirred for additional 30 min. The solution was poured into ice water,and extracted with EtOAc (×3). The organic layers were combined, washedwith H₂O (×3), brine (×3), dried over Na₂SO₄, filtered, and the filtratewas concentrated to yield 182 mg of1-(1-benzyl-5-chloro-1H-indole-2-yl)-2-methylpropan-1-ol.

Step 7.2-(1-(1-Benzyl-5-chloro-1H-indol-2-yl)-2-methylpropyl)isoindoline-1,3-dione

To a solution of1-(1-benzyl-5-chloro-1H-indole-2-yl)-2-methylpropan-1-ol (0.6 mmol),Ph₃P, (1 mmol), phthalimide (1.8 mmol) in 5 mL of dry THF at 0° C., wasadded DIAD (1 mmol) drop wise. The mixture was warmed up to roomtemperature gradually and stirred overnight. The solution was pouredinto water, and extracted with EtOAc (×3). The organic layers werecombined, washed with H₂O (×3), brine (×3), dried (Na₂SO₄), filtered,and the filtrate was concentrated. The material was purified by flashchromatography (10% EtOAc:hexane) to yield 170 mg of title compound.

Step 8. 1-(1-benzyl-5-chloro-1H-indole-2-yl)-2-methylpropan-1-amine

To a solution of product of step 7 (0.4 mmol) in 10 mL of EtOH, wasadded hydrazine (4 mmol) at 0° C. The mixture was stirred at 80° C.overnight. The solution was poured into water, and extracted with EtOAc(×3). The organic layers were combined, washed with 10% NaOH, H₂O (×3),brine (×3), dried (Na₂SO₄), filtered, and the filtrate was concentrated.The material was purified by flash chromatography (20% EtOAc:hexane) toyield 52 mg of1-(1-benzyl-5-chloro-1H-indole-2-yl)-2-methylpropan-1-amine.

Step 9

To a solution of1-(1-benzyl-5-chloro-1H-indole-2-yl)-2-methylpropan-1-amine (0.44 mmol)in 10 mL of anhydrous DCM, was added aldehyde (0.44 mmol) and sodiumtriacetoxyborohydride (0.44 mmol) at 0° C. The mixture was stirred atroom temperature overnight. The solution was poured into 10% aq. NaOH,and extracted with EtOAc (×3). The organic layers were combined, washedwith H₂O (×3), brine (×3), dried (Na₂SO₄), filtered, and the filtratewas concentrated. The material was purified by flash chromatography (20%EtOAc:hexane) to yield 40 mg of title compound.

Step 10.N-(1-(1-benzyl-5-chloro-1H-indol-2-yl)-2-methylpropyl)-N-(3-(1,3-dioxoisoindolin-2-yl)propyl)benzamide

To a solution of product of step 9 (0.1 mmol) in 2 mL of anhydrous DCMat 0° C., was added DMAP (0.01 mmol), Et₃N (0.4 mmol), and p-toluoylchloride (0.4 mmol). The mixture was stirred at room temperature for 1h. The solution was poured into water, and extracted with EtOAc (×3).The organic layers were combined, washed with H₂O (×3), brine (×3),dried (Na₂SO₄), filtered, and the filtrate was concentrated. Thematerial was purified by flash chromatography (10% EtOAc:hexane) toyield 50 mg of title compound.

Step 11.N-(3-aminopropyl)-N-[1-(1-benzyl-5-chloro-1H-indol-2-yl)-2-methylpropyl]benzamide

To a solution of product of step 10 (50 mg) in 1 mL of EtOH was addedhydrazine (0.1 mL). The mixture was stirred at room temperature for 2 h.The solution was poured into water, and extracted with EtOAc (×3). Theorganic layers were combined, washed with 10% NaOH aq., H₂O (×3), brine(×3), dried (Na₂SO₄), filtered, and the filtrate was concentrated. Thematerial was purified preparatory HPLC to giveN-(3-aminopropyl)-N-[1-(1-benzyl-5-chloro-1H-indol-2-yl)-2-methylpropyl]benzamide.

Example 5N-(3-aminopropyl)-N-[1-(1-benzyl-5-chloro-1H-indol-2-yl)-2-methylpropyl]-4-methylbenzamide(Compound 46)

The title compound was synthesized using similar procedure as in Example4 using p-toluoyl chloride in place of benzoyl chloride in step 10 ofExample 4.

Example 6N-(3-aminopropyl)-N-{1-[5-chloro-1-(phenylsulfonyl)-1H-indol-2-yl]-2-methylpropyl}-4-methylbenzamide(Compound 47)

The title compound was synthesized using similar procedure as in Example4 using 1-(5-chloro-1-phenylsulfonylindole)-2-methylpropan-1-ol (productof step 2 of example 4) in place of1-(1-benzyl-5-chloro-1H-indole-2-yl)-2-methylpropan-1-ol in step 7 ofexample 4.

The compounds in the table below may be prepared using the methodologydescribed in the previous Examples and Methods. The following tablesalso include compounds described in the experimental section. Thestarting materials used in the synthesis were recognizable to one ofskill in the art and were commercially available or were prepared usingknown methods. The compounds were named using ACD/Name Batch Version5.04 (Advanced Chemistry Development Inc.; Toronto, Ontario;www.acdlabs.com). TABLE 3 Compound Structure MH+ Name 1

475.3 N-(3-aminopropyl)-N-[(1R)-1-(1- benzyl-1H-benzimidazol-2-yl)-2-methylpropyl]-4-chlorobenzamide 2

455.2 N-(3-aminopropyl)-N-[(1R)-1-(1- benzyl-1H-benzimidazol-2-yl)-2-methylpropyl]-4-methylbenzamide 3

468.64 N-(3-aminopropyl)-N-[(1R)-1-(1-benzyl-5-methyl-1H-benzimidazol-2- yl)-2-methylpropyl]-4-methylbenzamide4

489.06 N-(3-aminopropyl)-N-[(1R)-1-(1-benzyl-5-chloro-1H-benzimidazol-2-yl)- 2-methylpropyl]-4-methylbenzamide5

507.1 N-(3-aminopropyl)-N-{(1R)-1-[1-(4- chlorobenzyl)-6-fluoro-1H-benzimidazol-2-yl]-2-methylpropyl}-4- methylbenzamide 6

475.3 N-(3-aminopropyl)-N-[(1R)-1-(1- benzyl-5-chloro-1H-benzimidazol-2-yl)propyl]-4-methylbenzamide 7

521.0 N-(3-aminopropyl)-N-[(1R)-1-(1- benzyl-1H-benzimidazol-2-yl)-2-methylpropyl]-4-bromobenzamide 8

535.3 N-(3-aminopropyl)-N-[(1R)-1-(1-benzyl-5-bromo-1H-benzimidazol-2-yl)- 2-methylpropyl]-4-methylbenzamide9

505.0 N-(3-aminopropyl)-N-[(1R)-1-(1- benzyl-5-bromo-1H-benzimidazol-2-yl)propyl]benzamide 10

519.1 N-(3-aminopropyl)-N-[(1R)-1-(1- benzyl-5-bromo-1H-benzimidazol-2-yl)propyl]-4-methylbenzamide 11

485.4 N-(3-aminopropyl)-N-{(1R)-1-[1-(3- hydroxybenzyl)-5-methyl-1H-benzimidazol-2-yl]-2-methylpropyl}-4- methylbenzamide 12

487.2 N-(3-aminopropyl)-N-{(1R)-1-[1-(3- fluorobenzyl)-5-methyl-1H-benzimidazol-2-yl]-2-methylpropyl}-4- methylbenzamide 13

483.2 N-(3-aminopropyl)-N-[(1R)-1-(1-benzyl-5-ethyl-1H-benzimidazol-2-yl)- 2-methylpropyl]-4-methylbenzamide14

499.2 N-(3-aminopropyl)-N-{(1R)-1-[5- ethyl-1-(3-hydroxybenzyl)-1H-benzimidazol-2-yl]-2-methylpropyl}-4- methylbenzamide 15

501.2 N-(3-aminopropyl)-N-{(1R)-1-[5- ethyl-1-(3-fluorobenzyl)-1H-benzimidazol-2-yl]-2-methylpropyl}-4- methylbenzamide 16

535.1 N-1-[(1R)-1-(1-benzyl-5-bromo-1H-benzimidazol-2-yl)-2-methylpropyl]-N-1-(4-methylbenzyl)-beta-alaninamide 17

481.2 N-(3-aminopropyl)-N-[(1R)-1-(1-benzyl-5-vinyl-1H-benzimidazol-2-yl)- 2-methylpropyl]-4-methylbenzamide18

485.2 N-(3-aminopropyl)-N-[(1R)-1-(1-benzyl-5-methoxy-1H-benzimidazol-2-yl)-2-methylpropyl]-4-methylbenzamide 19

531.2 N-(3-aminopropyl)-N-[(1R)-1-(1-benzyl-5-phenyl-1H-benzimidazol-2-yl)- 2-methylpropyl]-4-methylbenzamide20

564.1 2-(beta-alanylamino)-N-[(1R)-1-(1-benzyl-5-bromo-1H-benzimidazol-2-yl)- 2-methylpropyl]-4-methylbenzamide21

442.2 (3R,5R)-5-[1-(3-hydroxybenzyl)-5-methyl-1H-benzimidazol-2-yl]-1-(4- methylbenzoyl)pyrrolidin-3-ol 22

479.2 N-(3-aminopropyl)-N-[(1R)-1-(1-benzyl-5-ethynyl-1H-benzimidazol-2-yl)-2-methylpropyl]-4-methylbenzamide 23

546.1 2-(2-aminoethyl)-3-[(1R)-1-(1-benzyl-5-bromo-1H-benzimidazol-2-yl)-2- methylpropyl]-7-methylquinazolin-4(3H)-one 24

505.2 N-(3-aminopropyl)-3-fluoro-N-{(1R)-1-[1-(3-fluorobenzyl)-5-methyl-1H- benzimidazol-2-yl]-2-methylpropyl}-4-methylbenzamide 25

473.2 N-(3-aminopropyl)-N-{(1R)-1-[1-(3- fluorobenzyl)-5-methyl-1H-benzimidazol-2-yl]-2- methylpropyl}benzamide 26

509.1 N-(3-aminopropyl)-2,4-difluoro-N-{(1R)-1-[1-(3-fluorobenzyl)-5-methyl- 1H-benzimidazol-2-yl]-2-methylpropyl}benzamide 27

501.1 N-(3-aminopropyl)-N-{(1R)-1-[1-(3- fluorobenzyl)-5-methyl-1H-benzimidazol-2-yl]-2-methylpropyl}- 3,4-dimethylbenzamide 28

590.0 N-((1R)-1-{1-[3- (acetylamino)benzyl]-5-bromo-1H-benzimidazol-2-yl}-2-methylpropyl)-N- (3-aminopropyl)-4-methylbenzamide29

509.1 N-(3-aminopropyl)-2,6-difluoro-N-{(1R)-1-[1-(3-fluorobenzyl)-5-methyl- 1H-benzimidazol-2-yl]-2-methylpropyl}benzamide 30

491.2 N-(3-aminopropyl)-2-fluoro-N-{(1R)-1-[1-(3-fluorobenzyl)-5-methyl-1H- benzimidazol-2-yl]-2-methylpropyl}benzamide 31

553.0 N-(3-aminopropyl)-N-{(1R)-1-[5- bromo-1-(3-chlorobenzyl)-1H-benzimidazol-2-yl]-2- methylpropyl}benzamide 32

518.2 N-(3-aminopropyl)-N-{(1R)-1-[1-(3- fluorobenzyl)-5-methyl-1H-benzimidazol-2-yl]-2-methylpropyl}-4- nitrobenzamide 33

474.2 N-(3-aminopropyl)-N-{(1R)-1-[1-(3- fluorobenzyl)-5-methyl-1H-benzimidazol-2-yl]-2- methylpropyl}nicotinamide 34

474.2 N-(3-aminopropyl)-N-{(1R)-1-[1-(3- fluorobenzyl)-5-methyl-1H-benzimidazol-2-yl]-2- methylpropyl}isonicotinamide 35

523.2 N-(3-aminopropyl)-N-{(1R)-1-[1-(3- fluorobenzyl)-5-methyl-1H-benzimidazol-2-yl]-2-methylpropyl}-2- naphthamide 36

487.2 N-(3-aminopropyl)-N-{(1R)-1-[1-(3- fluorobenzyl)-5-methyl-1H-benzimidazol-2-yl]-2,2- dimethylpropyl}benzamide 37

489.2 N-(3-aminopropyl)-N-{(1R)-1-[1-(3- fluorobenzyl)-5-methyl-1H-benzimidazol-2-yl]-2-methylpropyl}-4- hydroxybenzamide 38

579.2 N-[3-(benzylamino)propyl]-N-[(1R)-1-(1-benzyl-5-chloro-1H-benzimidazol- 2-yl)-2-methylpropyl]-4-methylbenzamide 39

585.3 N-[(1R)-1-(1-benzyl-5-chloro-1H-benzimidazol-2-yl)-2-methylpropyl]-N-{3-[(cyclohexylmethyl)amino]propyl}- 4-methylbenzamide 40

455.2 N-(3-aminopropyl)-N-[(1R)-1-(1- benzyl-1H-benzimidazol-2-yl)-2,2-dimethylpropyl]benzamide 41

531.2 N-[(1R)-1-(1-benzyl-5-chloro-1H-benzimidazol-2-yl)-2-methylpropyl]-N- [3-(isopropylamino)propyl]-4-methylbenzamide 42

545.16 N-[(1R)-1-(1-benzyl-5-chloro-1H-benzimidazol-2-yl)-2-methylpropyl]-N- [3-(diethylamino)propyl]-4-methylbenzamide 43

543.2 N-[(1R)-1-(1-benzyl-5-chloro-1H-benzimidazol-2-yl)-2-methylpropyl]-N- [3-(cyclobutylamino)propyl]-4-methylbenzamide 44

557.0 N-(3-aminopropyl)-N-{(1R)-1-[5- bromo-1-(3,5-difluorobenzyl)-1H-benzimidazol-2-yl]-2- methylpropyl}benzamide 45

474.1 N-(3-aminopropyl)-N-[1-(1-benzyl-5- chloro-1H-indol-2-yl)-2-methylpropyl]benzamide 46

488.2 N-(3-aminopropyl)-N-[1-(1-benzyl-5-chloro-1H-indol-2-yl)-2-methylpropyl]- 4-methylbenzamide 47

538.1 N-(3-aminopropyl)-N-{1-[5-chloro-1-(phenylsulfonyl)-1H-indol-2-yl]-2- methylpropyl}-4-methylbenzamide 48

557.1 N-{3- [(aminocarbonyl)(cyano)amino]propyl}-N-[(1R)-1-(1-benzyl-5-chloro-1H- benzimidazol-2-yl)-2-methylpropyl]-4-methylbenzamide 49

532.1 N-{3-[(aminocarbonyl)amino]propyl}-N-[(1R)-1-(1-benzyl-5-chloro-1H- benzimidazol-2-yl)-2-methylpropyl]-4-methylbenzamide 50

496.2 N-{(1R)-1-[1-(3-fluorobenzyl)-5- methyl-1H-benzimidazol-2-yl]-2-methylpropyl}-N-(1H-imidazol-4- ylmethyl)benzamide

Example 7 Assay for Determining KSP Activity

This example provides a representative in vitro assay for determiningKSP activity in vitro. Purified microtubules obtained from bovine brainwere purchased from Cytoskeleton Inc. (Denver, Colo., USA). The motordomain of human KSP (Eg 5, KNSL1) was cloned, expressed, and purified togreater than 95% homogeneity. Biomol Green was purchased from AffinityResearch Products Ltd. (Matford Court, Exeter, Devon, United Kingdom).Microtubules and KSP motor protein (i.e., the KSP motor domain) werediluted in assay buffer (20 mM Tris-HCl (pH 7.5), 1 mM MgCl₂, 10 mM DTTand 0.25 mg/mL BSA) to a final concentration of 35 μg/mL microtubulesand 45 nM KSP. The microtubule/KSP mixture was then pre-incubated at 37°C. for 10 min to promote the binding of KSP to microtubules.

To each well of the testing plate (384-well plate) containing 1.25 μL ofinhibitor or test compound in DMSO (or DMSO only in the case ofcontrols) were added 25 μL of ATP solution (ATP diluted to aconcentration of 300 μM in assay buffer) and 25 μL of theabove-described microtubule/KSP solution. The plates were incubated atroom temperature for 1 h. Following incubation, 65 μL of Biomol Green (amalachite green-based dye that detects the release of inorganicphosphate) was added to each well. The plates were incubated for anadditional 5 to 10 min then the absorbance at 630 nm was determinedusing a Victor II plate reader. The amount of absorbance at 630 nmcorresponded to the amount of KSP activity in the samples. The IC₅₀ ofeach inhibitor or test compound was then determined based on thedecrease in absorbance at 630 nm at each concentration, via nonlinearregression using either XLFit for Excel or Prism data analysis softwareby GraphPad Software Inc.

Preferred compounds of the invention have a biological activity asmeasured by an IC₅₀ of less than about 1 mM in assay protocols describedin Example 7 above, with preferred embodiments having biologicalactivity of less than about 25 μM, with particularly preferredembodiments having biological activity of less than about 1000 nM, andwith the most preferred embodiments having biological activity of lessthan about 100 nM.

Example 8 Inhibition of Cellular Proliferation in Tumor Cell LinesTreated with KSP Inhibitors

Cells are plated in 96-well plates at densities of about 500 cells perwell of a 96-well plate and are allowed to grow for 24 hours. The cellsare then treated with various concentrations of compounds for 72 hours.Then, 100 μl of CellTiter Glo is added. CellTiter Glo is atetrazolium-based assay using the reagent 3-(4,5-dimethylthiazol-2-yl)5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) (U.S.Pat. No. 5,185,450) (see Promega product catalog #G3580, CeIITiter 96Aqueous One Solution Cell Proliferation Assay). The cells are thenincubated in the dark for 30 minutes. The amount of luminescence isdetermined for each well using a Walloc Trilux plate reader, whichcorrelates with the number of cells per well. The number of viable cellsin the wells that receive only DMSO (0.5%) serve as an indication of 0%inhibition, while wells without cells serve as 100% inhibition of cellgrowth. The compound concentration that resulted in a 50% growthinhibition (GI₅₀) is determined graphically from sigmoidal dose-responsecurves of log-transformed dose values versus cell counts (percent ofcontrol) at 72 hours of continuous compound exposure.

The cell lines used are listed below.

The cell proliferation assay is performed as described above.

Cancer Cell Lines

Colo 205—colon carcinoma

-   -   RPMI 1640+10% FBS+1% L-glutamine+1% P/S+1% NaPyr.+Hepes    -   +4.5 g/L Glucose+1% NaBicarb.

MDA 435—breast cancer—high met

-   -   EMEM+10% FBS+1% P/S+1% L-Glutamine+1% NEAA+1% NaPyr+1% vitamins

HCT-15 and HCT116—colon carcinoma

-   -   RPMI 1640+10% FBS+1% L-glutamine+1% P/S

Drug Resistant Cell Lines

KB3.1—colon epidermal carcinoma; parental cell line

-   -   Iscove's+10% FBS+1% L-glutamine+1% P/S

KBV1—p-glycoprotein associated multi-drug resistant cell line

-   -   RPMI 1640+10% FBS+1% L-glutamine+1% P/S+0.2 ug/ml Vinblastine

KB85—p-glycoprotein associated multi-drug resistant cell line

-   -   DMEM+10% FBS+1% L-glutamine+1% P/S+10 ng/ml Colchicine

Preferred compounds of the invention have a biological activity asmeasured by an GI₅₀ of less than about 1 mM in assay protocols describedwith some embodiments having biological activity of less than about 25μM, with other embodiments having biological activity of less than about1000 nM, and with still other embodiment having a GI₅₀ of less thanabout 100 nM.

Example 9 Clonogenic Softagar Assay Protocol

Human cancer cells are plated at a density of 3×10⁵ cells per well in a6-well plate. The next day, a compound of interest at a certainconcentration is added to each well. After 24 and 48 hours ofincubation, the cells are harvested, washed and counted. The followingsteps are performed using the Multimek 96 robot. Then, 500 viable cellsper well are plated in a 96-well plate that is coated with PolyHema toprevent attachment of the cells to the bottom of the well. Agarose (3%stock) is melted, diluted in warmed media and added to the cells to afinal concentration of 0.5%. After the soft agar solidified, the platesare incubated at 37° C. for 6 days. Alamar blue dye is added to cellsand plates are incubated for an additional 6 hours. The optical densitychange is measured on a Tecan plate reader and is considered tocorrelate with the number of colonies formed in soft agar. A cancerouscell is able to grow on the agar and thus will show an increase inoptical density. A reading of decreased optical density means that thecancer cells are being inhibited. It is contemplated that compounds ofthis invention will exhibit a decrease in optical density.

1. A compound of formula I:

wherein: W is ═CH— or ═N—; R¹ is selected from the group consisting ofaminoacyl, acylamino, carboxyl, carboxyl ester, aryl, and alkyloptionally substituted with hydroxy or halo; R² is selected from thegroup consisting of hydrogen, optionally substituted alkyl, and aryl; R³is —X-A, wherein A is selected from the group consisting of alkyl, aryl,heteroaryl, heterocyclic, and cycloalkyl, all of which may be optionallysubstituted with 1 to 4 substituents independently selected from thegroup consisting of alkyl, substituted alkyl, acylamino, heterocyclic,substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy,acyl, carboxyl, carboxyl ester, oxo (except as a substituent onsubstituted aryl or substituted heteroaryl), halo, hydroxy, and nitro; Xis selected from the group consisting of —C(O)—, —C(S)—, —S(O)—,—S(O)₂—, and —S(O)₂NR—, where R is hydrogen or alkyl and when X is—C(O)—, A is further selected from the group consisting of amino,substituted amino, alkoxy, and substituted alkoxy; R⁴ is selected fromthe group consisting of hydrogen, hydroxy, acyl, alkyl, substitutedalkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, heterocyclic, and substitutedheterocyclic; or R¹ and R⁴, together with the carbon atom attached to R¹and the nitrogen atom attached to R⁴ form a group selected from thegroup consisting of heterocyclic, substituted heterocyclic, heteroaryl,and substituted heteroaryl; or when R¹ and R⁴, together with the carbonattached to R¹ and nitrogen atom attached to R⁴ do not form a groupselected from the group consisting of heterocyclic, substitutedheterocyclic, heteroaryl, and substituted heteroaryl, then R³ and R⁴,together with the nitrogen atom bound thereto, form a group selectedfrom the group consisting of heterocyclic, substituted heterocyclic,heteroaryl, and substituted heteroaryl; R⁵ is -L-A¹ where L is selectedfrom the group consisting of —S(O)_(r)— where r is one or two and C₁ toC₂ straight chain alkylene, optionally substituted with hydroxy, haloand acylamino; A¹ is selected from the group consisting of aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic,substituted heterocyclic, cycloalkyl and substituted cycloalkyl; each R⁶is independently selected from the group consisting of acyl, acylamino,alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, alkoxy, substituted alkoxy, amino, substitutedamino, aminoacyl, aryl, substituted aryl, aryloxy, substituted aryloxy,carboxyl, carboxyl ester, cyano, cycloalkyl, substituted cycloalkyl,halo, heteroaryl, substituted heteroaryl, heteroaryloxy, substitutedheteroaryloxy, heterocyclic, substituted heterocyclic, heterocyclyloxy,substituted heterocyclyloxy, hydroxy, nitro, thiol, alkylthio,substituted alkylthio, arylthio, substituted arylthio, heteroarylthio,and substituted heteroarylthio; p is equal to 0, 1, 2 or 3; orpharmaceutically acceptable salts, esters and prodrugs thereof; with theproviso that when W is ═N—, and A¹ is substituted phenyl, saidsubstituted phenyl does not include an ortho substituent of the formula-Q-NR⁷R⁸ where Q is a bond, C₁ to C₃ alkyl, C₂ to C₃ alkenyl, C₂ to C₃alkynyl and R⁷ and R⁸ are independently C₁ to C₈ alkyl or C₁ to C₈cycloalkyl optionally substituted with 1 to 3 substituents selected fromthe group consisting of hydroxy, halo, amino, cyano, nitro, C₁ to C₈alkyl, C₁ to C₈ cycloalkyl, halo C₁ to C₈ alkyl, C₁ to C₈ alkoxy, haloC₁ to C₈ alkoxy, or R⁷ and R⁸ jointly with the nitrogen atom to whichthey are bound form an optionally substituted 3- to 7-memberedheterocyclic or an optionally substituted 3- to 7-membered heteroaryl.2. The compound of claim 1, wherein the compound is of formula IA:

wherein R¹, R², R³, R⁴, R⁵, R⁶ and p are as defined above.
 3. Thecompound of claim 1, wherein the compound is of formula IB:

wherein R¹, R², R³, R⁴, R⁵, R⁶ and p are as defined above.
 4. A compoundof formula IC:

wherein W is ═CH— or ═N—; p is equal to 0, 1, 2 or 3; R⁹ is alkyl orsubstituted alkyl; R¹¹ is —X¹-A², wherein X¹ is —C(O)— and A² isselected from the group consisting of alkyl, substituted alkyl, aryl,substituted aryl, heteroaryl, and substituted heteroaryl; R¹² isselected from the group consisting of hydrogen, -alkylene-amino,-alkylene-substituted amino, -alkylene-aryl, -alkylene-substituted aryl,-alkylene-heteroaryl, and -alkylene-substituted heteroaryl; or R⁹ andR¹² together with the carbon atom attached to R⁹ and the nitrogen atomattached to R¹² form a group selected from the group consisting ofheterocyclic, substituted heterocyclic, heteroaryl, and substitutedheteroaryl; or when R⁹ and R¹² together with the carbon atom attached toR⁹ and the nitrogen atom attached to R¹² do not form a group selectedfrom the group consisting of heterocyclic, substituted heterocyclic,heteroaryl, and substituted heteroaryl, then R¹¹ and R¹², together withthe nitrogen atom bound thereto join to form a group selected from thegroup consisting of heterocyclic, substituted heterocyclic, heteroaryl,and substituted heteroaryl; R¹³ is -L¹-A³, wherein L¹ is —S(O)_(r)—where r is 1 or 2 or C₁ to C₂ straight chain alkylene, and A³ isselected from the group consisting of aryl, substituted aryl,heteroaryl, and substituted heteroaryl; each R¹⁴ is independentlyselected from the group consisting of halo, C₂ to C₃ alkynyl, C₂ to C₃alkenyl, C₁ to C₅ alkyl, C₁ to C₃ alkoxy, and phenyl; orpharmaceutically acceptable salts, esters or prodrugs thereof; with theproviso that when W is ═N—, and A¹ is substituted phenyl, saidsubstituted phenyl does not include an ortho substituent of the formula-Q-NR⁷R⁸ where Q is a bond, C₁ to C₃ alkyl, C₂ to C₃ alkenyl, C₂ to C₃alkynyl and R⁷ and R⁸ are independently C₁ to C₈ alkyl or C₁ to C₈cycloalkyl optionally substituted with 1 to 3 substituents selected fromthe group consisting of hydroxy, halo, amino, cyano, nitro, C₁ to C₈alkyl, C₁ to C₈ cycloalkyl, halo C₁ to C₈ alkyl, C₁ to C₈ alkoxy, haloC₁ to C₈ alkoxy, or R⁷ and R⁸ jointly with the nitrogen atom to whichthey are bound form an optionally substituted 3- to 7-memberedheterocyclic or an optionally substituted 3- to 7-membered heteroaryl.5. The compound of claim 1, wherein R¹ is alkyl or aryl.
 6. The compoundof claim 5, wherein R¹ is selected from the group consisting of ethyl,isopropyl, t-butyl, and phenyl.
 7. The compound of claim 1, wherein R²is hydrogen or methyl.
 8. The compound of claim 1, wherein X is —C(O)—and A is aryl or heteroaryl optionally substituted with a substituentselected from the group consisting of halo, alkyl, acylamino, nitro,hydroxy.
 9. The compound of claim 1, wherein R³ is selected from thegroup consisting of (2-chloro-6-methylpyridin-4-yl)carbonyl;(5-methylimidazol-4-yl)carbonyl; (dimethylamino)methyl carbonyl;(naphth-2-yl)carbonyl; (pyridin-3-yl)carbonyl; (pyridin-4-yl)carbonyl;1,5-dimethylpyrazol-3-ylcarbonyl;1-methyl-5-trifluoromethylpyrazol-4-ylcarbonyl;1-methyl-5-chloropyrazol-4-ylcarbonyl;2-(2-aminoethylamido)-4-methylbenzoyl; 2,4-difluorobenzoyl;2,4-dimethylthiazol-5-ylcarbonyl; 2,6-difluorobenzoyl;2-aminoethylcarbonyl; 2-aminothiazol-4-ylcarbonyl; 2-chlorobenzoyl;2-chloropyridin-5-ylcarbonyl; 2-fluorobenzoyl; 2-methoxybenzoyl;2-methylpyridin-5-ylcarbonyl; 3,4-dichlorobenzoyl; 3,4-dimethylbenzoyl;3-chlorobenzoyl; 3-fluoro-4-methylbenzoyl;3-hydroxypyridin-4-ylcarbonyl; 4-aminopyridin-3-ylcarbonyl;4-bromobenzoyl; 4-chlorobenzoyl; 4-chloropyridin-3-ylcarbonyl;4-dimethylaminobenzoyl; 4-hydroxybenzoyl; 4-hydroxypyridin-3-ylcarbonyl;4-methoxybenzoyl; 4-methyl-2-(aminoethylcarbonylamino)benzoyl;4-methylbenzoyl; 4-methylisoxazol-3-ylcarbonyl;4-methylpyridin-3-ylcarbonyl; 4-morpholino-N-ylpyridin-3-ylcarbonyl;4-nitrobenzoyl; 4-t-butylbenzoyl; 4-trifluoromethylbenzoyl;4-trifluoromethylpyridin-3-ylcarbonyl; 5-chloropyridin-3-ylcarbonyl;5-methylpyrazol-3-ylcarbonyl; 6-chloropyridin-3-ylcarbonyl; benzoyl;cyclohexylcarbonyl; furan-3-ylcarbonyl; isoxazol-3-ylcarbonyl;phenylsulfonyl; piperidin-4-ylcarbonyl; pyrazin-2-ylcarbonyl;pyridazin-3-ylcarbonyl; pyridazin-4-ylcarbonyl;tetrahydrofuran-2-ylcarbonyl; tetrahydrofuran-3-ylcarbonyl; andthiazol-4-ylcarbonyl.
 10. The compound of claim 1, wherein R³ isselected from the group consisting of:


11. The compound of claim 9, wherein R³ is selected from the groupconsisting of 2-aminoethylcarbonyl;4-methyl-2-(aminoethylcarbonylamino)benzoyl; (naphth-2-yl)carbonyl;(pyridin-3-yl)carbonyl; (pyridin-4-yl)carbonyl;2-(2-aminoethylamido)-4-methylbenzoyl; 2,4-difluorobenzoyl;2,6-difluorobenzoyl; 2-fluorobenzoyl; 3,4-dimethylbenzoyl;3-fluoro-4-methylbenzoyl; 4-bromobenzoyl; 4-chlorobenzoyl;4-hydroxybenzoyl; 4-methylbenzoyl; 4-nitrobenzoyl; and benzoyl.
 12. Thecompound of claim 1, wherein R¹ and R⁴, together with the carbon atomattached to R¹ and the nitrogen atom attached to R⁴ form a heterocyclicor substituted heterocyclic group.
 13. The compound of claim 12, whereinthe substituted heterocyclic group is 3-hydroxy-pyrrolidinyl.
 14. Thecompound of claim 1, wherein R³ and R⁴ together with the nitrogen atomattached thereto join to form a substituted heterocyclic group.
 15. Thecompound of claim 14, wherein the heterocyclic group is2-aminoethyl-5-methyl-8-oxo-7H-quinazolin-1-yl.
 16. The compound ofclaim 1, wherein R⁴ is selected from the group consisting of hydrogen,alkyl and substituted alkyl.
 17. The compound of claim 1, wherein R⁴ isselected from the group consisting of hydrogen;(aminomethylcarbonyl)aminoethyl;2,2-dimethyl-3-(4-methylpiperazin-1-yl)propyl;2,2-dimethyl-3-dimethylaminopropyl; 2-aminoethyl;2-hydroxyethyl-3-aminopropyl; 2-hydroxypyridin-4-ylmethyl;2-hydroxypyridin-5-ylmethyl; 3-(1-cyanourea)propyl;3-(benzylamino)propyl; 3-(cyclobutylamino)propyl;3-(cyclohexylmethylamino)propyl; 3-(diethylamino)propyl;3-(isopropylamino)propyl; 3-(phenylcarbonyloxy)propyl;3-[(3-trifluoromethylpyridin-6-yl)amino]propyl;3-[(5-pyridin-3-yloxyindazol-3-yl)methylamino]propyl;3-[(6-fluoroindazol-3-yl)methylamino]propyl;3-[(aminomethyl-carbonyl)amino]propyl; 3-[5-cyanopyridin-2-yl]propyl;3-{[5-(pyridin-3-yloxy)indazol-3-yl]methylamino]propyl;3-amino-3-(aminocarbonyl-methyl)propyl; 3-aminopropyl; 3-hydroxypropyl;3-methylsulfonylaminopropyl; 3-ureapropyl; 4-methylbenzyl;5-methoxyindazol-3-ylmethyl; benzyl; piperidin-3-ylmethyl;piperidin-4-yl; and pyrrolidin-2-ylmethyl.
 18. The compound of claim 1,wherein R⁴ is selected from the group consisting of:


19. The compound of claim 16, wherein R⁴ is selected from the groupconsisting of hydrogen; 3-(1-cyanourea)propyl; 3-(benzylamino)propyl;3-(cyclobutylamino)propyl; 3-(cyclohexylmethylamino)propyl;3-(diethylamino)propyl; 3-(isopropylamino)propyl; 3-aminopropyl;3-ureapropyl; 4-methylbenzyl; and imidazol-4-ylmethyl.
 20. The compoundof claim 1, wherein L is —SO₂— or —CH₂— and A¹ is optionally substitutedaryl.
 21. The compound of claim 1, wherein R⁵ is selected from the groupconsisting of 2,4-difluorobenzyl; 2-methylbenzyl; 3-(methylamido)benzyl;3,5-difluorobenzyl; 3-chlorobenzyl; 3-fluorobenzyl; 3-hydroxybenzyl;3-methylbenzyl; 4-chlorobenzyl; 4-methylbenzyl; benzyl; andthiazol-4-ylmethyl.
 22. The compound of claim 1, wherein R⁵ groups areselected from the group consisting of: 3-(methylamido)benzyl;3,5-difluorobenzyl; 3-chlorobenzyl; 3-fluorobenzyl; 3-hydroxybenzyl;4-chlorobenzyl; and benzyl.
 23. The compound of claim 1, wherein p is 1.24. The compound of claim 23, wherein R⁶ is selected from the groupconsisting of propargyl; bromo; —CF₃; chloro; ethyl; ethynyl; fluoro;methoxy; methyl; phenyl; and vinyl.
 25. The compound of claim 1, whereinR⁶ is selected from the group consisting of bromo; chloro; ethyl;methoxy; methyl; propargyl; vinyl; fluoro; and phenyl.
 26. The compoundof claim 1, wherein p is
 0. 27. A compound selected from the groupconsisting of:N-(3-aminopropyl)-N-[(1R)-1-(1-benzyl-1H-benzimidazol-2-yl)-2-methylpropyl]-4-chlorobenzamide;N-(3-aminopropyl)-N-[(1R)-1-(1-benzyl-1H-benzimidazol-2-yl)-2-methylpropyl]-4-methylbenzamide;N-(3-aminopropyl)-N-[(1R)-1-(1-benzyl-5-methyl-1H-benzimidazol-2-yl)-2-methylpropyl]-4-methylbenzamide;N-(3-aminopropyl)-N-[(1R)-1-(1-benzyl-5-chloro-1H-benzimidazol-2-yl)-2-methylpropyl]-4-methylbenzamide;N-(3-aminopropyl)-N-{(1R)-1-[1-(4-chlorobenzyl)-6-fluoro-1H-benzimidazol-2-yl]-2-methylpropyl}-4-methylbenzamide;N-(3-aminopropyl)-N-[(1R)-1-(1-benzyl-5-chloro-1H-benzimidazol-2-yl)propyl]-4-methylbenzamide;N-(3-aminopropyl)-N-[(1R)-1-(1-benzyl-1H-benzimidazol-2-yl)-2-methylpropyl]-4-bromobenzamide;N-(3-aminopropyl)-N-[(1R)-1-(1-benzyl-5-bromo-1H-benzimidazol-2-yl)-2-methylpropyl]-4-methylbenzamide;N-(3-aminopropyl)-N-[(1R)-1-(1-benzyl-5-bromo-1H-benzimidazol-2-yl)propyl]benzamide;N-(3-aminopropyl)-N-[(1R)-1-(1-benzyl-5-bromo-1H-benzimidazol-2-yl)propyl]-4-methylbenzamide;N-(3-aminopropyl)-N-{(1R)-1-[1-(3-hydroxybenzyl)-5-methyl-1H-benzimidazol-2-yl]-2-methylpropyl}-4-methylbenzamide;N-(3-aminopropyl)-N-{(1R)-1-[1-(3-fluorobenzyl)-5-methyl-1H-benzimidazol-2-yl]-2-methylpropyl}-4-methylbenzamide;N-(3-aminopropyl)-N-[(1R)-1-(1-benzyl-5-ethyl-1H-benzimidazol-2-yl)-2-methylpropyl]-4-methylbenzamide;N-(3-aminopropyl)-N-{(1R)-1-[5-ethyl-1-(3-hydroxybenzyl)-1H-benzimidazol-2-yl]-2-methylpropyl}-4-methylbenzamide;N-(3-aminopropyl)-N-{(1R)-1-[5-ethyl-1-(3-fluorobenzyl)-1H-benzimidazol-2-yl]-2-methylpropyl}-4-methylbenzamide;N-1-[(1R)-1-(1-benzyl-5-bromo-1H-benzimidazol-2-yl)-2-methylpropyl]-N-1-(4-methylbenzyl)-beta-alaninamide;N-(3-aminopropyl)-N-[(1R)-1-(1-benzyl-5-vinyl-1H-benzimidazol-2-yl)-2-methylpropyl]-4-methylbenzamide;N-(3-aminopropyl)-N-[(1R)-1-(1-benzyl-5-methoxy-1H-benzimidazol-2-yl)-2-methylpropyl]-4-methylbenzamide;N-(3-aminopropyl)-N-[(1R)-1-(1-benzyl-5-phenyl-1H-benzimidazol-2-yl)-2-methylpropyl]-4-methylbenzamide;2-(beta-alanylamino)-N-[(1R)-1-(1-benzyl-5-bromo-1H-benzimidazol-2-yl)-2-methylpropyl]-4-methylbenzamide;(3R,5R)-5-[1-(3-hydroxybenzyl)-5-methyl-1H-benzimidazol-2-yl]-1-(4-methylbenzoyl)pyrrolidin-3-ol;N-(3-aminopropyl)-N-[(1R)-1-(1-benzyl-5-ethynyl-1H-benzimidazol-2-yl)-2-methylpropyl]-4-methylbenzamide;2-(2-aminoethyl)-3-[(1R)-1-(1-benzyl-5-bromo-1H-benzimidazol-2-yl)-2-methylpropyl]-7-methylquinazolin-4(3H)-one;N-(3-aminopropyl)-3-fluoro-N-{(1R)-1-[1-(3-fluorobenzyl)-5-methyl-1H-benzimidazol-2-yl]-2-methylpropyl}-4-methylbenzamide;N-(3-aminopropyl)-N-{(1R)-1-[1-(3-fluorobenzyl)-5-methyl-1H-benzimidazol-2-yl]-2-methylpropyl}benzamide;N-(3-aminopropyl)-2,4-difluoro-N-{(1R)-1-[1-(3-fluorobenzyl)-5-methyl-1H-benzimidazol-2-yl]-2-methylpropyl}benzamide;N-(3-aminopropyl)-N-{(1R)-1-[1-(3-fluorobenzyl)-5-methyl-1H-benzimidazol-2-yl]-2-methylpropyl}-3,4-dimethylbenzamide;N-((1R)-1-{1-[3-(acetylamino)benzyl]-5-bromo-1H-benzimidazol-2-yl}-2-methylpropyl)-N-(3-aminopropyl)-4-methylbenzamide;N-(3-aminopropyl)-2,6-difluoro-N-{(1R)-1-[1-(3-fluorobenzyl)-5-methyl-1H-benzimidazol-2-yl]-2-methylpropyl}benzamide;N-(3-aminopropyl)-2-fluoro-N-{(1R)-1-[1-(3-fluorobenzyl)-5-methyl-1H-benzimidazol-2-yl]-2-methylpropyl}benzamide;N-(3-aminopropyl)-N-{(1R)-1-[5-bromo-1-(3-chlorobenzyl)-1H-benzimidazol-2-yl]-2-methylpropyl}benzamide;N-(3-aminopropyl)-N-{(1R)-1-[1-(3-fluorobenzyl)-5-methyl-1H-benzimidazol-2-yl]-2-methylpropyl}-4-nitrobenzamide;N-(3-aminopropyl)-N-{(1R)-1-[1-(3-fluorobenzyl)-5-methyl-1H-benzimidazol-2-yl]-2-methylpropyl}nicotinamide;N-(3-aminopropyl)-N-{(1R)-1-[1-(3-fluorobenzyl)-5-methyl-1H-benzimidazol-2-yl]-2-methylpropyl}isonicotinamide;N-(3-aminopropyl)-N-{(1R)-1-[1-(3-fluorobenzyl)-5-methyl-1H-benzimidazol-2-yl]-2-methylpropyl}-2-naphthamide;N-(3-aminopropyl)-N-{(1R)-1-[1-(3-fluorobenzyl)-5-methyl-1H-benzimidazol-2-yl]-2,2-dimethylpropyl}benzamide;N-(3-aminopropyl)-N-{(1R)-1-[1-(3-fluorobenzyl)-5-methyl-1H-benzimidazol-2-yl]-2-methylpropyl}-4-hydroxybenzamide;N-[3-(benzylamino)propyl]-N-[(1R)-1-(1-benzyl-5-chloro-1H-benzimidazol-2-yl)-2-methylpropyl]-4-methylbenzamide;N-[(1R)-1-(1-benzyl-5-chloro-1H-benzimidazol-2-yl)-2-methylpropyl]-N-{3-[(cyclohexylmethyl)amino]propyl}-4-methylbenzamide;N-(3-aminopropyl)-N-[(1R)-1-(1-benzyl-1H-benzimidazol-2-yl)-2,2-dimethylpropyl]benzamide;N-[(1R)-1-(1-benzyl-5-chloro-1H-benzimidazol-2-yl)-2-methylpropyl]-N-[3-(isopropylamino)propyl]-4-methylbenzamide;N-[(1R)-1-(1-benzyl-5-chloro-1H-benzimidazol-2-yl)-2-methylpropyl]-N-[3-(diethylamino)propyl]-4-methylbenzamide;N-[(1R)-1-(1-benzyl-5-chloro-1H-benzimidazol-2-yl)-2-methylpropyl]-N-[3-(cyclobutylamino)propyl]-4-methylbenzamide;N-(3-aminopropyl)-N-{(1R)-1-[5-bromo-1-(3,5-difluorobenzyl)-1H-benzimidazol-2-yl]-2-methylpropyl}benzamide;N-(3-aminopropyl)-N-[1-(1-benzyl-5-chloro-1H-indol-2-yl)-2-methylpropyl]benzamide;N-(3-aminopropyl)-N-[1-(1-benzyl-5-chloro-1H-indol-2-yl)-2-methylpropyl]-4-methylbenzamide;N-(3-aminopropyl)-N-{1-[5-chloro-1-(phenylsulfonyl)-1H-indol-2-yl]-2-methylpropyl}-4-methylbenzamide;N-{3-[(aminocarbonyl)(cyano)amino]propyl}-N-[(1R)-1-(1-benzyl-5-chloro-1H-benzimidazol-2-yl)-2-methylpropyl]-4-methylbenzamide;N-{3-[(aminocarbonyl)amino]propyl}-N-[(1R)-1-(1-benzyl-5-chloro-1H-benzimidazol-2-yl)-2-methylpropyl]-4-methylbenzamide;N-{(1R)-1-[1-(3-fluorobenzyl)-5-methyl-1H-benzimidazol-2-yl]-2-methylpropyl}-N-(1H-imidazol-4-ylmethyl)benzamide;and pharmaceutically acceptable salts, esters, and prodrugs thereof. 28.A pharmaceutical composition comprising a therapeutically effectiveamount of a compound of claim 1 and a pharmaceutically acceptablecarrier.
 29. The composition of claim 28 further comprising at least oneadditional agent for the treatment of cancer.
 30. The composition ofclaim 29, wherein the additional agent for the treatment of cancer isselected from the group consisting of irinotecan, topotecan,gemcitabine, imatinib, trastuzumab, 5-fluorouracil, leucovorin,carboplatin, cisplatin, docetaxel, paclitaxel, tezacitabine,cyclophosphamide, vinca alkaloids, anthracyclines, rituximab, andtrastuzumab.
 31. A method of treating a disorder mediated, at least inpart, by KSP in a mammalian patient comprising administering to amammalian patient in need of such treatment a therapeutically effectiveamount of a composition of claim
 28. 32. The method of claim 31, whereinthe disorder is a cellular proliferative disease.
 33. The method ofclaim 32, wherein the cellular proliferative disease is cancer.
 34. Themethod of claim 33, wherein the cancer is selected from the groupconsisting of lung and bronchus; prostate; breast; pancreas; colon andrectum; thyroid; stomach; liver and intrahepatic bile duct; kidney andrenal pelvis; urinary bladder; uterine corpus; uterine cervix; ovary;multiple myeloma; esophagus; acute myelogenous leukemia; chronicmyelognous leukemia; lymphocytic leukemia; myeloid leukemia; brain; oralcavity and pharynx; larynx; small intestine; non-hodgkin lymphoma;melanoma; and villous colon adenoma.
 35. The method of claim 34 furthercomprising administering to the mammalian patient one additional agentfor the treatment of cancer.
 36. The method of claim 35, wherein theadditional agent for the treatment of cancer is selected from the groupconsisting of irinotecan, topotecan, gemcitabine, imatinib, trastuzumab,5-fluorouracil, leucovorin, carboplatin, cisplatin, docetaxel,paclitaxel, tezacitabine, cyclophosphamide, vinca alkaloids,anthracyclines, rituximab, and trastuzumab.
 37. A method for inhibitingKSP kinesin in a mammalian patient, wherein said method comprisesadministering to the patient an effective KSP-inhibiting amount of acompound of claim
 1. 38. Use of the composition of claim 28 in themanufacture of a medicament for the treatment of cancer.